Processes and intermediates for making 16-phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives and their stereoisomers

ABSTRACT

This invention relates to a process for making a compound of formula I ##STR1## in the form of a stereoisomer or mixture thereof, wherein R is hydrogen, lower alkyl; X is hydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, and the wavy lines represent the α or β configuration with the proviso that when one wavy line is α the other is β, or a pharmaceutically acceptable, non-toxic salt of the compound wherein R is hydrogen; novel intermediates useful for preparing these compounds; processes for making the intermediates; and a stereoisomer of the compound of formula I wherein R is methyl and X is hydrogen and a process for making same.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 564,386, filed Dec. 22, 1983, now allowed, which is herebyincorporated in full by reference.

BACKGROUND OF THE INVENTION

The present invention relates to a process for making compounds in theform of a stereoisomer or mixture thereof, of 16-phenoxy and 16-(o, m orp)-substituted phenoxy prostaglandin derivatives represented by thefollowing formula ##STR2## wherein R is hydrogen, lower alkyl; X ishydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, and thewavy lines represent the α or β configuration with the proviso that whenone wavy line is α the other is β, or a pharmaceutically acceptable,non-toxic salt of the compound wherein R is hydrogen; certain novelintermediates for making these compounds and a stereoisomer of thecompound of formula I wherein R is methyl and X is hydrogen and aprocess for preparing same.

The compounds of formula I are disclosed in U.S. Pat. No. 4,178,457.

The synthesis described herein addresses the twin problems of how toprepare an individual stereoisomer of the subject compounds whileallowing selective deprotection of the C-9 hydroxyl group so it can beoxidized without also oxidizing the C-11 and C-15 groups and that thesubsequent deprotection of C-11 and C-15 will not degrade the resultingmolecule.

The problem of preparing an individual stereoisomer is solved by goingthrough a novel propargyl alcohol intermediate which, though it is madeas a diastereomeric mixture, can be separated into its twostereochemically pure isomers. One isomer of this stereochemically purepropargyl alcohol is then converted to a single, stereochemically pureallenic compound by employing a stereospecifichomologation/rearrangement reaction in the next step. Starting with aspecific stereochemically pure phenoxy lactone compound, which isavailable in the art, one can open the lactone and convert the resultingacid to an aldehyde. This novel aldehyde is reacted with a metalacetylide to give a propargyl alcohol having two stereoisomers. The twoisomers can be separated into two stereochemically pure fractions bychromatographic means where one has properly selected one ether-formingprotecting groups at C-9, C-11 and C-15, particularly at C-9. It hasbeen found that a bulky ether-forming group at C-9 is necessary toeffect readily this separation. For example, when the C-9 hydroxylprotecting group is an appropriate alkyl, aryl or arylalkyl substitutedsilyl ether, separation of the two propargyl alcohol isomers may bereadily effected where otherwise separation is usually difficult andincomplete. The second essential step is to convert one stereochemicallypure isomer to a single stereochemically pure allene-containingcompound. This is accomplished by a hologation/rearrangement reactionusing a trialkyl orthoacetate reagent and temperature.

The other problem is to design a synthetic sequence which will allowselective deprotection of the C-9 hydroxyl group so it can be oxidized,and then removal of the C-11 and C-15 hydroxyl protection groups withoutdecomposing the resulting molecule. This is accomplished here byprotecting C-9 with a base-labile ether-forming group while protectingC-11 and C-15 with base-stabile ether-forming groups. Then it ispossible to drop off the C-9 protecting group, oxidize the hydroxylgroup and then deprotect C-11 and C-15 under mild acid conditions. Thissequence is essential because base would cause elimination-rearrangementto the "B" type prostaglandin and catalytic hydrogenation would affectthe allene group.

The described process also provides an efficient method of preparing thecompounds of U.S. Pat. No. 4,178,457, in particular in the form ofmixtures of the four components which are included in formula I asdefined below.

The compounds of U.S. Pat. No. 4,178,457 are known to be useful in thetreatment of mammals where prostaglandins are indicated. They areparticularly useful as inhibitors of gastric secretion. It has also beenfound that the stereoisomer of the compound of formula I possessing theR allene configuration wherein R is methyl and X is hydrogen having thefollowing structure ##STR3## has excellent biological properties (forexample potency, low toxicity etc.) and other properties which affectits pharmaceutical use (for example chemical stability, shelf lifeetc.). A study conducted in rats showed that the antisecretory ED₅₀ forthis individual R allenic stereoisomer is about 6 μg/Kg.

Furthermore, this R allenic stereoisomer occurs in crystalline form.

Prostaglandins often are oily materials. The racemic diastereoisomericmixture of the compounds of formula I wherein R is methyl and X ishydrogen is known to be a viscous oil (see U.S. Pat. No. 4,178,457) orlow melting waxy solid. The compound which is structurally closest tothe R allene stereoisomer of formula I' and its racemicdiastereoisiomeric mixture, namely (dl)9α,11α,15α-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid methyl ester (a compound in Example 16 of U.S. Pat. No. 3,985,791)also occurs as an oil. The R allenic stereoisomer of formula I' wasfirst obtained as an oil, but when stored in the freezer to bestabilized, surprisingly, the oily material spontaneously crystallized.The crystallized material has a melting point above 70° C. In contrastwith this isomer, the corresponding racemic diastereoisiomeric mixture,when stored in the freezer under the same conditions, takes about 1-3weeks to become waxy solid. The S allene stereoisomer corresponding toformula I' never crystallized under similar conditions.

In addition, it was reported in UK Pat. No. 1,288,174, U.S. Pat. No.4,005,133 and EPO Publication No. 97,439 that in order to havefree-flowing crystalline solid materials, prostaglandins had to beconverted into their organic or inorganic salts. Therefore, it is alsosurprising that the R allenic stereoisomer of formula I', without beingconverted into a salt, is a free-flowing crystalline material.

The crystalline material of formula I' can be easily purified usingconventional techniques. The crystallinity of this material facilitateshandling and chemical analysis and improves chemical stability.Furthermore, the crystalline material of formula I' can be readilyformulated into solid dosage forms.

DEFINITIONS

Formulas having an allene group are represented herein as havingsubstituents on one end of the allene group which are oriented at 90° tothose on the other. A broken line indicates that the substituent isbehind the plane of the allene group and is designated as being in the αconfiguration. A triangular line defines the substituent as being infront or the plane of the allene group and is referred to as being inthe β configuration. When there are at least three different groupssubstituted on the allene, as in formula I, the allene moiety isrendered asymmetric.

The broken lines shown in the above formula and other formulas herein atcarbons 8, 9, 11 and 15 indicate that the pendent substituents are inthe α configuration, i.e., below the plane of the cyclopentane ring orof the lower side chain. The triangular shaped line at C-12 denotes theβ configuration, i.e. that the substituent is above the plane of thecyclopentane ring.

The double bond at C-13 in these formulas has the trans configuration,the same as do the natural PGE and PGF series prostaglandins.

The compounds of this invention possess asymmetric centers and thus canbe produced as racemic or non-racemic mixtures or as individual R- orS-enantiomers. The individual enantiomers may be obtained by resolving aracemic or non-racemic mixture of an intermediate at some appropriatestage of the synthesis. It is understood that the racemic or non-racemicmixtures and the individual R- or S-enantiomers are encompassed withinthe scope of the present invention.

Formula I includes any single structure below (Ia, Ia', Ib and Ib'), allpermutations of two or three components in any proportions, and mixturesof all four components in any proportions. ##STR4##

Any individual component may be prepared by processes described belowstarting from the appropriate individual enantiomers of the lactone offormula 1 in the reaction scheme on page 11. Mixtures of Ia and Ia', Iband Ib', Ia and Ib, Ia' and Ib' and mixtures of the four components mayalso be prepared by processes described below. Mixtures of Ia and Ia' orIb and Ib' or mixtures of all four components are produced starting fromthe racemic or non-racemic modifications of the lactone of formula 1.Mixtures of Ia and Ib, or Ia' and Ib' are prepared starting from theappropriate optically active lactone of formula 1. All the mixturesabove the mixtures of Ia and Ib' and Ib and Ia' may also be prepared bymixing the appropriate intermediates or individual components obtainedby the processes described below. Any mixtures of three components maybe prepared by mixing the appropriate intermediates or individualcomponents obtained by the processes described below.

For the sake of simplicity only one enantiomer, i.e., the enantiomerhaving the natural prostaglandin configuration will be depicted in thedescription of the process; however, it is to be understood that theracemic and non-racemic mixtures and the individual unnaturalenantiomers are also encompassed thereby, they being obtained bystarting with the corresponding racemic or non-racemic mixture orunnatural enantiomer.

The natural configurations are represented by the formula Ia and Ib. Theunnatural configurations are represented by the formula Ia' and Ib'.

The term "mixture", as applied to formula I is defined in the presentapplication as any combination of all four components (of formula Ia,Ia' Ib and Ib' as depicted above) in any proportions and allpermutations of any two or three of the four components in anyproportions. As applied to synthetic intermediates of formulas II-VIIIin the claims (or formulas 8-17 in the reaction scheme on pages 11-12),the term "mixture" is defined in the present application as anycombination of the stereoisomers implied by the wavy lines and theenantiomers of such stereoisomers in any proportions.

The use of the symbol "R" preceding a substituent designates theabsolute stereochemistry of that substituent according to theCahn-Ingold-Prelog rules [see Cahn et al., Angew. Chem. Inter. Edit.,Vol. 5, p. 385 (1966), errata p. 511; Cahn et al., Angew. Chem., Vol.78, p. 413 (1966); Cahn and Ingold, J. Chem. Soc., (London), 1951, p.612; Cahn et al., Experientia, Vol. 12, p. 81 (1956); Cahn J. Chem.Educ., Vol. 41, p. 116 (1964)]. Because of the interrelation of thedesignated substituent with the other substituents in a compound havingα or β prefixes, the designation of the absolute configuration of onesubstituent fixes the absolute configuration of all substituents in thecompound and thus the absolute configuration of the compound as a whole.

"Isomers" are different compounds that have the same molecular formula.

"Stereoisomers" are isomers that differ only in the way the atoms arearranged in space.

"Enantiomers" are a pair of stereoisomers that are non-superimposablemirror images of each other.

"Diastereoisomers" are stereoisomers which are not mirror-images of eachother.

"Epimers" are diastereomers which differ only in the configuration ofone asymmetric center.

"Racemic mixture" means a mixture containing equal parts of individualenantiomers. "Non-racemic mixture" is a mixture containing unequal partsof individual enantiomers.

For the purpose of this invention, the terms "lower alkyl" or "alkyl"mean a straight or branched alkyl radical of 1 to 6 carbon atoms.Examples of such radicals are methyl, ethyl, propyl, isopropyl, butyl,t-butyl, i-butyl, sec-butyl, pentyl, hexyl and the like. Lower alkoxymeans an --OR radical wherein R is lower alkyl. Halo refers to fluoro,chloro, bromo and iodo. Aryl refers to aryl groups wherein the ringsystem contains 6-10 carbon atoms not counting substituents, such asphenyl, naphthyl or the like. Lower alkyl aryl refers to an aryl groupas defined above having a lower alkyl chain wherein lower alkyl isdefined above. Substituted lower alkyl aryl refers to a radical whereinthe aryl group defined above of a lower alkyl aryl defined above issubstituted with one or more lower alkyl, halo, or lower alkoxy radicalsas these latter terms are defined above.

The term "w/v%" (percent weight in volume) indicates the number of g ofa constituent in 100 ml of solution.

The term "pharmaceutically acceptable, non-toxic salts" refers to thosebase-derived salts of any compound herein having a carboxylic acidfunction. These salts are derived from pharmaceutically acceptable,non-toxic inorganic or organic bases.

Salts derived from inorganic bases include sodium, potassium, lithium,ammonium, calcium, magnesium, ferrous, zinc, copper, manganous,aluminum, ferric, manganic salts and the like. Particularly preferredare the ammonium, potassium, sodium, calcium and magnesium salts. Saltsderived from pharmaceutically acceptable organic, non-toxic basesinclude salts of primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic aminesand basic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic non-toxic bases are isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline and caffeine.

The acid salts of these compounds, where appropriate to make, areprepared by treating the corresponding free acids of the compounds withat least one molar equivalent of a pharmaceutically acceptable base.Representative pharmaceutically acceptable bases are sodium hydroxide,potassium hydroxide, ammonium hydroxide, calcium hydroxide,trimethylamine, lysine, caffeine, and the like. The reaction isconducted in water, alone or in combination with an inert,water-miscible organic solvent, at a temperature of from about 0° C. toabout 100° C., preferably at room temperature. Typical inert,water-miscible organic solvents include methanol, ethanol, or dioxane.The molar ratio of compounds of formula I to base used are chosen toprovide the ratio desired for any particular salt.

The numbering of these compounds follows that in use for the naturallyoccuring PGE and PGF compounds, illustrated as follows: ##STR5##

For analytical purposes, in this disclosure a carbon of a particularintermediate is identified by the number it will have in the finalproduct, ie formula I. Thus, for example, in formula 8 in the ReactionScheme below, the carbon on which the R² ether group is substituted isdesignated C-9 as that is the numbering of that carbon in formula I.

The process for preparing the instant compounds, including the novelintermediates is outlined in the following reaction scheme. ##STR6##

In the preceding flow sheet R¹ is a base-stabile, acid-labileether-forming group as defined below, R² is a base-labile ether-formingradical as defined below and M is hydrogen or a metal ion such as analkali metal ion.

DETAILED DESCRIPTION OF THE PROCESS

The starting material, formula 1, can be prepared according to theprocedures set forth in U.S. Pat. Nos. 3,880,712, 3,985,791, and4,304,907, which procedures are incorporated herein by reference andmade a part hereof.

Before opening the lactone ring of formula 1, the two hydroxyl groupsare converted to ethers. These two groups are designated R¹ and definedas base-stabile, acid-labile ether-forming groups. Such a group may beany ether-forming group which will not be hydrolyzed when treated with astrong aqueous base such a sodium or potassium hydroxide, yet will behydrolyzed by acid under mild conditions, conditions which will not notresult in degradation of the product, formula I. Examples of groupswhich are base-stabile yet acid-labile are tetrahydrofuranyl,tetrahyropyranyl, 2-ethoxyethyl and the like. Excluded from thisdefinition are alkyl ethers, benzyl ether and alkylaryl ethers, and thelike. The conditions normally required to effect acid hydrolysis ofthese latter ethers would cause product degradation during thehydrolysis process, if in fact their hydrolysis would be effected byacid at all.

It is preferred to protect the C-11 and C-15 hydroxyl groups withtetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl. Ether formationwith any of these groups is generally carried out in an aprotic solventsuch as a halogenated hydrocarbon with an acid catalyst using amountsand conditions well known in the art. Preferably the acid catalyst isemployed in amounts up to 5% by weight of the reactants. Mostpreferably, the ether-forming reagent will be dihydropyran, at leastabout 2.1 equivalents, the reaction being carried out in methylenechloride in the presence of p-toluenesulfonic acid. The reaction isgenerally carried out at between 20°-50° C., preferably at ambienttemperature over a period of 15 minutes to four hours preferably abouttwo hours.

Hydrolytic cleavage of the lactone ring is effected by means of a base,preferably an aqueous alkali metal base in a polar organic solvent. Anaqueous solution of base such as lithium hydroxide, sodium hydroxide,potassium hydroxide, or the like, is added to a polar organic solventcontaining the lactone, all under an inert atmosphere, e.g. nitrogen.The concentration of the added base preferably will be about 1-4M, morepreferably between 2.8-3M. A slight molar excess of base is used,preferable 1.05 moles per mole of lactone. Potassium hydroxide is thepreferred base. The aqueous base solution is added under nitrogen to apremade solution of the lactone in a solvent such as tetrahydrofuran ora simple alcohol such as methanol. The hydrolysis is effected betweenroom temperature and 100° C., preferably by heating the solution atreflux under nitrogen. It is advantageous to monitor the reaction'sprogress by thin layer chromatography (tlc).

The hydroxyl group generated by hydrolysis of the lactone is convertedto an ether using a reagent which will give a base-labile ether. Thisgroup is designated R² and is defined as a base-labile ether-forminggroup. This group is best exemplified by --SiR₄ R₅ R₆ where R₄, R₅ andR₆ are alkyl, phenyl or arylalkyl except that all three may not besimultaneously methyl. For the purpose of this invention, alkyl means aradical of 1 to 6 carbon atoms. Arylalkyl is a radical wherein alkyl hasthe same meaning as lower alkyl and aryl is exemplified by but notlimited to phenyl, alkyl substituted phenyl, and naphthyl. Particularlypreferred silyl groups are t-butyldimethylsilyl, triisopropylsilyl,triphenylsilyl, t-butyldiphenylsilyl and2,4,6-tri-t-butylphenoxydimethylsilyl radicals.

When a silylating agent is employed, standard conditions normally usedfor such a reagent are used. For example, the reaction is generallycarried out in a polar aprotic solvent with an excess of the silylatingreagent, 2.2 to 4 equivalents, and an excess relative to the silylatingreagent of some nitrogen-containing compound such as imidazole.Silylation is usually carried out between 0° and 50° C.

Preferably, 6 equivalents imidazole and about 3 equivalents oft-butyldimethylsilyl chloride will be added to dry dimethylformamidesolution of the hydroxy acid salt and stirred overnight at about roomtemperature. Preferably, completion of the reaction will be confirmed bytlc. This reaction gives the silyl ether as well as the silyl ester ofthe acid. Because the silyl ester is not desired, it is hydrolyzed insitu without being isolated by adding water to the reaction pot and thenrecovering the silyl ether compound in its free acid form.

The resulting free acid, represented by formula 4, is then converted tothe aldehyde of formula 7. This can be accomplished by any number ofappropriate methods, four of which are set out herein to exemplify thepreferred methods. In one instance, formula 4 is esterified to giveformula 5 which is then reduced to give the alcohol of formula 6, thatbeing oxidized to the aldehyde of formula 7. A second alternative is toreduce the free acid of formula 4 to the alcohol of formula 6 and thenoxidize the alcohol to the aldehyde (formula 7). Alternative threecomprises esterifying the free acid of formula 4 and then reducing theester directly to the aldehyde of formula 7. The fourth alternative isto first convert the free acid to the acid halide (acyl chloride) andthen effect a Rosenmund redunction to form the aldehyde.

In the first alternative, the first step is to esterify the free acid bystandard esterification procedures using, for example, either an alkyliodide or a diazoalkane reagent. The words alkyl and alkane here havethe same definition as that set forth above for lower alkyl.

When the reagent is an alkyl iodide, preferably methyl iodide, thereaction is carried out in an aprotic solvent such as dimethylformamideor dimethylacetamide containing a weak base such as sodium hydrogencarbonate. A large excess of the alkyl iodide is used, for example about7-10 equivalents and corresponding large equivalents of base. Thereaction is preferably carried out under an inert atmosphere, e.g.nitrogen and at a slightly elevated temperature not to exceed theboiling point of the alkyl iodide employed. If the reagent is methyliodide, the reaction is preferably carried out at a temperature of about40°-45° C. A number of hours are usually required to effect thereaction, usually 16 to 24 hours. Completion of the reaction can beconfirmed by tlc. If the reaction is not complete after the initialreaction period, an additional one equivalent of the alkyl iodide and acorresponding amount of base are added and the reaction continued asbefore. This procedure is repeated as often as necessary to complete thereaction.

If a diazoalkane is used, preferably diazomethane, the reaction iscarried out using standard procedures for generating diazomethane andfor reacting it with the free acid. See F. Arndt, Org. Syn. Coll. VolII, 165 (1943) and H. von Pechmann, Chem. Ber. 27, 1888 (1894) and 28,855 (1895).

In the second step of the first alternative, reduction of the carboxylicacid ester to the alcohol (formula 6) is effected by a metal hydridesuch as diisobutylaluminum hydride, lithium aluminum hydride or thelike. The reaction is carried out in a solvent compatible with theselected reducing agent and preferably under an inert atmosphere and ata temperature of less than 50° C. for a period of up to about 4 hours.

When the reducing agent is diisobutylaluminum hydride, the reaction iscarried out in toluene, benzene or a similar nonpolar solvent. Thediisobutylaluminum hydride in toluene is added to a cooled solution ofthe carboxylic acid ester after which the reaction solution is allowedto come to room temperature wherein the reaction is usually completeafter 30-45 minutes. A nominal 2.5 equivalents of diisobutylaluminumhydride is employed to effect the reduction. The reaction can bemonitored by tlc and, if not complete, additional hydride is added andstirring continued for an another 30 minutes or so. Unreacted hydride isdecomposed by adding water and an alkali metal salt such as sodiumfluoride or sodium sulfate.

Alternatively, the carboxylic acid ester may be reduced to the alcoholusing lithium aluminum hydride in a polar solvent such as ethyl ether,tetrahydrofuran or the like. Lithium aluminum hydride reduction iseffected using the same ratio of materials and same reaction conditionsas recited above for diisobutylaluminum hydride.

Oxidization of the alcohol to the aldehyde is carried out by means of amild oxidizing reagent. Any one of a number of mild oxidizing reagentsmay be used to effect this oxidation but it is preferred to use chromium(VI) trioxide, pyridinium dichromate, pyridinium chlorochromate or thelike but preferably chromium trioxide, in the presence of pyridine,hexamethylphosphoric triamide, 3,5-dimethylpyrazole or the like,preferably pyridine, or pyridinium chlorochromate with sodium acetate,and an organic solvent, e.g., dichloromethane, dichloroethane, and thelike preferably, dichloromethane or mixtures thereof at a temperaturefrom about -10° C. to about 30° C., preferably about 15° C. to about 25°C., for about 30 minutes to about 2 hours, preferably about 15 minutesto about 45 minutes, to obtain the aldehyde of formula 7.Advantageously, this reaction is carried out under anhydrous conditionsunder an inert atmosphere, e.g., nitrogen.

Alternative two is effected by simply reducing the free acid directly tothe alcohol and then oxidizing that compound to the aldehyde of formula7. The first step, reduction of the acid to the alcohol, is accomplishedby means of borane methyl sulfide. In this reaction, the methyl ester isdissolved in a polar solvent, the solution stabilized in a bath atbetween about 0°-25° C. and the system purged with dry nitrogen. Boranemethyl sulfide, about 3 equivalents is then added dropwise with stirringafter which stirring is continued for up to about 6 hours, preferablyabout 3.5 hours to effect the reaction.

Having obtained the alcohol, it is then oxidized to the aldehyde in themanner set forth above for oxidizing formula 6 to formula 7.

The third alternative comprises first esterifying the free acid offormula 4 by the methods described above and then reducing the ester,formula 5, directly to the aldehyde by means of diisobutylaluminumhydride at low temperature. The reaction is effected using the sameratio of reactants given above, but in this instance the reaction iscarried out at a temperature of about -70° C. or thereabouts.

In the fourth alternative, the free acid is reduced to the aldehyde byfirst converting the acid to its acid halide (chloride) by reacting theacid with thionyl chloride, phosphorus trichloride or oxalyl chloride ata temperature range between 0° and 30° C. and then carrying out aRosenmund reduction with H₂ and Palladium on barium sulfate at atemperature between 0° and 50° C., or its equivalent.

Formation of the propargyl alcohols, formula 8, is effected by means ofa metal acetylide in an appropriate anhydrous organic solvent such as ahalogenated alkane, an ether, a hydrocarbon or the like, preferablyunder an inert atmosphere such as nitrogen. To a preformed solution ofaldehyde in a solvent such as methylene chloride, dichloroethane,tetrahydrofuran, diethyl ether, toluene or the like, preferablymethylene chloride, is added an excess of a metal acetylide reagent,exemplified by ethynyl magnesium chloride, ethynyl magnesium bromide,ethynyl magnesium iodide, lithium acetylide ethylene diamine complex andethynyl lithium, under nitrogen. The preferred metal acetylide isethynyl magnesium chloride. The reaction is carried out at a temperaturebetween 0° and 50° C., preferably between 20°-30° C., until the reactionis complete (which can be confirmed by tlc), usually within 30 minutes,most usually within 5-10 minutes.

The mixture of propargyl alcohol epimers may be separated into fractionscontaining a single pure propargylic epimer by chromatographic means,for example, silica gel tlc or column chromatography with varyingmixtures of moderately polar solvents in non-polar solvents.

In case the mixtures of allene isomers (formulas Ia and Ib, or formulasIa' and Ib') or mixtures of all four components are desired, thisseparation step is omitted.

Conversion of the propargyl alcohol to the allene may be carried out byany reaction which effects a stereospecific homologation/rearrangement.By this means, a single propargyl alcohol epimer can be converted to asingle corresponding allenyl stereoisomer. Herein it is preferred toeffect this rearrangement by means of a Claisen type rearrangementemploying a lower trialkyl orthoacetate and a catalytic amount of a lowmolecular weight alkanoic acid, for example, acetic acid, propionic acidor the like. In this instance, a catalytic amount of acid is some amountless than 5% by volume relative to the volume of trialkyl orthoacetate.

The trialkyl orthoacetates which may be used are illustrated bytrimethyl or triethyl orthoacetate and the like. The propargylic alcoholis dissolved in the trialkyl orthoacetate, preferably under nitrogen,along with a catalytic amount of alkanoic acid, usually about a 1%volume relative to the orthoacetate. The orthoester reacts with thepropargyl alcohol to give a mixed trialkylorthoester which is notisolated but caused to rearrange in situ by heating the pot. Thereaction flask is immersed in a preheated oil bath, for example one atabout 150°-250° C., and stirred for a short period, about 30 minuteswhile maintaining the pot temperature between about 100°-130° C.,preferably between about 110°-120° C. During the heating period, amixture of orthoacetate and alkanoic acid, in the same ratio notedabove, is added to the system while concurrently distilling out of thereaction system an equivalent volume of trialkylorthoester-alkanol-acid. The reaction bath is preferably maintained at atemperature between about 170°-175° C. during the distillation process.The resulting product is the ester of formula 9.

To obtain the final product, it is necessary to add one carbon betweenthe allene group and the acid function of formula 9 (homologation) in amanner which will not affect the stereochemistry of the allene or othersites on the molecule. The desired homologue is represented by formula13. This homologation may be accomplished by a number of methods knownin the art. The preferred methods employ a strong base in the last stepof the homologation which will simultaneously cleave the R² group,giving the compounds of formula 13. Other reaction sequences requiretreatment with base after the homologue is formed in order to obtain theC-9 hydroxyl group of formula 13.

The alkyl ester generated by the Claisen rearrangement may behomologated by reducing the ester to its corresponding primary alcoholby some appropriate reducing reagent such as a metal hydride, e.g.lithium aluminum hydride, diisobutylaluminum hydride or the like. Thisalcohol is then converted to some functional group which is a goodleaving group and then treated with an alkali metal cyanide, followed bytreatment with a strong base to effect hydrolysis of both the nitrileand the R² group of C-9.

The leaving group to which the alcohol is converted may be, for examplea halo group such as bromo or chloro or a sulfonyl ester. The alcohol isconverted to the corresponding halo compound by a variety of methodsknown in the art. This product is then treated with cyanides such asalkali metal cyanide, for example sodium or potassium cyanide to makethe nitrile. The nitrile is then hydrolyzed by strong base, which alsoserves to hydrolyze the R² base-labile ether group.

Alternatively, the alcohol is treated with an alkyl or arylalkylsulfonyl ester forming reagent in preparation for making the nitrile.Such reagents are preferably methanesulfonyl chloride orp-toluenesulfonyl chloride or a similar sulfonyl halide. The sulfonylester is converted to the nitrile by means of an alkali metal cyanidesalt, preferably sodium or potassium cyanide. This nitrile is thentreated with strong base to effect formation of the acid whilesimultaneously hydrolyzing the R² group, which gives the compound offormula 13.

Another alternative is to reduce the ester function of formula 9 to analdehyde, carry out a Wittig reaction, hydrolyze, and oxidize theresulting homologated aldehyde and then treat the resulting acid withbase to effect hydrolysis of the R² group. In this sequence, the esterof formula 9 is reduced to its corresponding alcohol and oxidized to thealdehyde. Alternatively, the ester may be reduced directly to thealdehyde using diisobutylaluminum hydride at low temperature, e.g. -70°C. The resulting aldehyde is then treated with the phosphorus ylide(phenyl)₃ P═CHOCH₃ and then Hg(OAc)₂ /KI to give the aldehyde homologueof formula 14. This aldehyde is treated with a mild oxidizing agent, onelike the ones noted herein above, to obtain the protected acid. Thisprotected acid is then treated with a dilute solution of a strong baseto effect hydrolysis of the R² group. A full description of the basehydrolysis conditions is given herein below.

A third alternative is the Arndt-Eistert synthesis. For example, theester of formula 9 is converted to the acid halide (chloride) by meansof oxalyl chloride or thionyl chloride and then treated withdiazomethane to give the diazoketone. The diazoketone is then rearrangedto the homologated acid using silver oxide and water. This acid is thentreated with base to hydrolyze the R² group giving the compound offormula 13.

The preferred method for converting formula 9 to its homologue, formula13, is to first reduce the ester of formula 9 to its correspondingalcohol, form a sulfonyl ester of the alcohol, treat the sulfonyl esterwith an alkali metal cyanide to obtain the nitrile, and convert thenitrile to the acid by base hydrolysis while simultaneously hydrolyzingthe R² base-labile ether group.

In the preferred sequence, the acid ester of formula 9 is reduced to itscorresponding alcohol by means of a metal hydride under anhydrousconditions, preferably under an inert atmosphere. A dry aprotic polarsolvent such as absolute diethyl ether or the like is placed under a dryinert atmosphere and a reducing agent, for example a metal hydride suchas lithium aluminum hydride (LAH) or the like, is added (2.2 to 4equivalents) followed by the allenic ester. It is preferred to mix theseveral reaction ingredients at a reduced temperature, about 0°-15° C.,and then reflux the solution for 10-30 minutes or until tlc indicatesthe reaction is complete.

When reduction is complete, the reaction mixture is again cooled tobetween 0°-15° C. and excess reagent (LAH) is reacted with acarbonyl-containing compound such as acetone or ethyl acetate therebymoderating subsequent and complete decomposition; complete decompositionfollows addition of an aqueous complexing agent such as potassium sodiumtartrate or a similar aluminum complex-forming salt.

In order to prepare the nitrile, the primary alcohol made as per thepreceding paragraph is first converted to a alkyl- or arylalkylsulfonylester, for example the methanesulfonyl ester or p-toluenesulfonyl esterderivatives. The allenyl alcohol, dissolved in an anhydrous polarorganic solvent such as a halogenated alkane, i.e. methylene chloride,dichloroethane and the like is introduced into a reaction flask alongwith an anhydrous trialkylamine such as triethylamine. The reactionflask is purged with dry nitrogen and the reaction mixture cooled tobetween about -40° and 25° C. The sulfonyl ester-forming reagent, e.g.methanesulfonyl chloride, dissolved in the anhydrous organic solvent isthen added with stirring while maintaining the temperature of thereaction mixture at between about -40° to -20° C., preferably between-30° to -20° C. About a two fold molar excess of the ester-formingreagent is used. When addition of the sulfonyl ester-forming reagent iscompleted, about 15-30 minutes, the reaction mixture is stirred atbetween about -30° to -10° C. until the reaction is complete as can beindicated by tlc. When the reaction is completed, the cooling bath isremoved and additional trialkylamine is added, predissolved in theorganic solvent. A solution of aqueous sodium bicarbonate or a similarbase is then added with vigorous stirring in order to decompose excessester-forming reagent.

The nitrile is formed by means of an alkali metal cyanide, mostpreferably potassium cyanide. The reaction is carried out in a polarsolvent, for example, dimethyl sulfoxide, under an inert atmosphere at atemperature between 50°-120° C. for up to an hour. Dry conditions arepreferred.

The metal cyanide, about 5-8 equivalents, is first placed in a flaskunder an inert atmosphere such as nitrogen. Solvent is added and theflask placed in a bath preheated to about 75°-80° C. The intermediate,dissolved in the reaction solvent, is then added. Heating and stirringis continued for up to 2 hours, preferably 1 hour or until completion ofthe reaction as indicated by tlc.

Hydrolysis of the nitrile by base gives the salt (--COOM of formula 13),which may be acidified to obtain the free acid, and at the same timedeprotects the C-9 hydroxy group, which, as noted above is a base-labileether. These hydrolysis are effected with a dilute solution of a strongbase such as one of the alkali metal hydroxide bases, e.g. lithiumhydroxide, sodium hydroxide, potassium hydroxide and the like. A dilutesolution is one which has a concentration of 0.05 to 2M., preferablyabout 0.5M. An appropriate solvent is, for example, 2-methoxyethanol ora similar polar solvent which is miscible with water. Preferably, aninert atmosphere is maintained. In terms of temperature and time thereaction is effected by heating the solvent to reflux for up to about 72hours.

Preferably these hydrolysis will be effected by charging a reactionflask with the solvent and reactant, adding the base, predissolved inwater, and then purging the system with nitrogen. The reaction mixtureis then refluxed for about 60 hours. The cooled reaction mixture is thenneutralized before isolation of the 9-hydroxy-1-acid product.

The acids of formulas 13 and 15 are esterified by the same proceduresset forth herein above for esterifying formula 4.

Oxidation of the C-9 hydroxyl group is effected by a mild oxidizingagent such as those set forth herein above in the discussion relating tothe oxidation of formula 6. Preferably, the oxidizing reagent will bechromium trioxide (4.5-10 equivalents) and 3,5-dimethylpyrazole orCollins reagent (chromium trioxide and pyridine), the reaction beingcarried out under an inert atmosphere in a polar aprotic solvent.Reagens are combined with solvent at reduced temperature, about -30° C.to -10° C. with stirring to effect thorough mixing of the reagents. Thealcohol is then added in additional solvent, the initial reducedtemperature being maintained during the addition and for the remainderof the reaction period, usually about 1 to 2 hours. Preferably thereaction will be carried out in methylene chloride under dry nitrogenfor a period of about 1 hour.

Hydrolysis of the C-11 and C-15 blocking groups is effected by acid, forexample, a alkanoic acid of 1 to 6 carbon atoms, or a hydrogen halide.

When acetic acid is used, standard procedures well known in the art maybe used. For example, the standard hydrolysis procedure uses acetic acidand a polar solvent such a tetrahydrofuran or the like. The alkyl ester,glacial acetic acid, water and organic solvent are mixed in a flaskunder nitrogen and heated at low temperature, between about 20°-60° C.,preferably 40° C. for up to 16 hours, preferably 12 hours. The preferredreaction medium is 85-95 w/v% of 20-60 w/v% of aqueous glacial aceticacid with 5-15 w/v% of an organic solvent. Most preferably, the reactionmedium is 60 w/v% of water, 30 w/v% of acetic acid and 10 w/v% oftetrahydrofuran.

Alternatively, hydrolysis of the ether groups may be effected by ahydrogen halide, preferably an aqueous solution of the acid dispersed ina water immiscible solvent, preferrably with a scavenging agent to reactwith the released blocking groups, the reaction being effected at atemperature between -40° to 50° C. over a period of about 5 minutes to 4hours. This method comprises stirring an aqueous solution of hydrogenhalide with a water immiscible solvent in which the intermediate hasbeen dissolved. The hydrogen halide may be hydrogen fluoride, hydrogenchloride, hydrogen bromide or hydrogen iodide. The acid should bepresent in a slight molar excess, for example about at least 2.05equivalent of acid, though the reaction can be effected by using a largeexcess of acid, ie. up to 10 equivalents or more. Preferably 2.05 to 3.0equivalents will be used, most preferably about 2.5 equivalents. Anywater immiscible organic solvent may be used but it is preferred to usea halogenated hydrocarbon such as, for example, methylene chloride,dichloroethane and the like. To trap the released blocking group, areactive scavenging material is added to the reaction mixture. Thisscavenging material is preferably a mercaptan, for examplemercaptoethanol. The scavenging material is present in an amount of 2.0to 3.0 equivalents, preferably about 2.0 equivalents. The reaction iscomplete in about 30-60 minutes at a temperature between about -30° to50° C., preferably 10°-50° C.

When the R allene steveoisomer of formula I' ##STR7## is prepared,removal of the solvent under reduced pressure affords the product as anoil. The oily material spontaneously crystallizes when it is cooled to alower temperature, preferably at a temperature between -20° to 0° C.Purification of the crystalline material can be effected usingconventional recrystallization techniques.

The R allenic isomer of formula I' is extremely useful in the treatingand prevention of gastric and duodenal ulcers.

The R allenic isomer of formula I' can be administered in a wide varietyof dosage forms, either alone or in combination with otherpharmaceutically compatible medicaments, in the form of pharmaceuticalcompositions suited for oral or parenteral administration or inhalationin the case of bronchodilators. This compound is typically administeredas pharmaceutical compositions consisting essentially of the compoundand a pharmaceutical carrier. The pharmaceutical carrier can be either asolid material, liquid or aerosol, in which the compound is dissolved,dispersed or suspended, and can optionally contain small amounts ofpreservatives and/or pH buffering agents. Suitable preservatives whichcan be used include, for example, benzyl alcohol or the like. Suitablebuffering agents include, for example, sodium acetate and pharmaceuticalphosphate salts or the like.

The liquid compositions can, for example, be in the form of solutions,emulsions, suspensions, syrups, or elixirs. The solid compositions cantake the form of tablets, powders, capsules, pills or the like,preferably in unit dosage forms for simple administration or precisedosages. Suitable solid carriers include, for example, pharmaceuticalgrades of starch, lactose, sodium saccharine, talcum, sodium bisulfiteor the like.

For inhalation administration, the R allenic isomer of formula I' can,for example, be administered as an aerosol comprising this compound inan inert propellant together with a cosolvent, e.g., methanol, togetherwith optional preservatives and buffering agents. Additional generalinformation concerning the inhalation administration of aerosols can behad by reference to U.S. Pat. Nos. 2,868,691 and 3,095,355.

The precise effective dosage of the R allene isomer of formula I' willvary depending upon the mode of administration, condition being treatedand host.

To further illustrate and exemplify the practice of this invention, thefollowing non-limiting Examples are provided.

EXAMPLE 1(1α-Hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)cyclopent-2α-yl)aceticacid lactone

A 1 liter round bottom flask equipped with a magnetic stirring bar andDrierite® drying tube was charged with 16.5 g of(1α,4α-dihydroxy-3β-(3α-hydroxy-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)aceticacid lactone, 500 ml of methylene chloride, 8.8 ml of dihydropyran and afew crystals of p-toluenesulfonic acid.H₂ O. This mixture was stirred atroom temperature for 2 hours. Two drops of triethylamine were added andthe solution stirred for 2 minutes. The reaction mixture was washed with1×50 ml of saturated aqueous sodium chloride and dried over sodiumsulfate. Evaporation of the solvent gave a residue which was taken up ina minimum amount of ethyl acetate and charged onto a 7.5 cm diametercolumn filled with 500 g of silica gel packed in pure hexane. The columnwas then eluted with a gradient of 20% to 40% ethyl acetate in hexane.Appropriate fractions were combined and stripped to dryness to affordthe title compound.

Proceeding in a similiar manner, but substituting for the startingcompound in the preceding paragraph the appropriately substitutedphenoxylactone, the following compounds may be prepared:

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(m-trifluoromethylphenoxy)-1(E)-buten-1-yl)cyclopent-2α-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(m-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(o-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(p-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(p-chlorophenoxy)-(1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(o-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(m-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(m-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(o-bromophenoxy)-1(E)-buten-1-yl)cyclopent-2α-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(p-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(m-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(o-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(p-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-tetrahydropyran-2-yloxy)-4-(m-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone;

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-(o-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone; and

(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-p-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)aceticacid lactone.

EXAMPLE 2 Potassium(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-(buten-1-yl)-cyclopent-2α-yl)-acetate

A reaction flask equipped with a magnetic stirrer and reflux condensertopped with a nitrogen inlet was charged with 25 ml of tetrahydrofuranand 5 g of(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)aceticacid lactone. The suspension was stirred until the reactant haddissolved during which time the flask was vacuum purged with nitrogen. A3.82 ml aliquot of 2.91M KOH/H₂ O was added and the reaction flask againvacuum purged with nitrogen. This solution was then refluxed undernitrogen until the reaction was completed (monitored by tlc). The cooledsolution was stripped to dryness, dissolved in 50 ml of toluene andstripped to dryness under vacuum to provide the title compound.

Proceeding in a similiar manner, but replacing the starting materialwith an analog from Example 1, all compounds prepared as per Example 1are converted to the corresponding potassium salt.

EXAMPLE 3(1α-t-Butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-aceticacid

A 7.76 g aliquot of potassium(1α-hydroxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)acetatewas introduced into a reaction flask and 25 ml of dry dimethylformamideadded. Imidazole, 4.32 g, was added to the stirred mixture followed by a4.7 aliquot of t-butyldimethylsilyl chloride. The reaction was stirredovernight at room temperature after which 5 ml of water was added withvigorous stirring for 30 to 45 minutes. The product was recovered byextraction with diethyl ether, followed by a saturated aqueous sodiumchloride wash, after which the solution was dried over sodium sulfateand the solvent removed under reduced pressure. The residue was furtherpurified by passing it through a 350 ml "C" sintered glass filter funnelpacked with 95 g silica gel slurried in 10% v/v ethyl acetate/hexane,the free acid being eluted with 1 L of 10% ethyl acetate/hexane.Appropriate fractions were combined and the solvent removed to give thetitle compound.

By the same method, the compounds prepared in Example 2 are converted tothe corresponding t-butyldimethylsilyl ether compounds.

EXAMPLE 4 Methyl(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)acetate

Dry dimethylformamide, 80 ml, and 6.24 g of(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)aceticacid, 3.00 g NaHCO₃ and 12.01 g methyl iodide were introduced into areaction flask equipped with a stirrer and reflux condenser topped withN₂ /vac/septum inlet. The flask was vacuum purged five times withnitrogen and then heated to between 40°-45° C. and stirred overnight.Additional methyl iodide (1.46 g) was added and the reaction continuedat 40°-45° C. over a second night. Water, 500 ml, was then added to thereaction mixture which was then extracted with 3×50 ml of methylenechloride. The combined methylene chloride layers were further dilutedwith an equal volume of hexane. The resulting organic layer was washedwith water (2×50 ml), saturated sodium chloride (1×50 ml) and dried oversodium sulfate. Evaporation of the solvent afforded a residue which wasfurther purified by silica gel column chromatography. The silica gel wasprepared in 15% ethyl acetate/hexane and the compound eluted with thatsolvent mixture. Combined appropriate fractions were stripped to drynessto give the title compound.

Proceeding in the same manner, but substituting for the startingcompound named herein, the compounds prepared in Example 3, eachcompound prepared in that Example may be converted to its methyl ester.

EXAMPLE 5(1α-t-Butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-2-ethanol-1-ol

Into a reaction flask fitted with a N₂ /vac/septum inlet was introduced53 ml of dry toluene in which was dissolved 5.3 g of methyl(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)cyclopent-2α-yl)acetate.The reaction was cooled in an ice bath and vacuum purged five times withnitrogen. Using a dry syringe transfer technique, 21.4 ml ofdiisobutylaluminum hydride, 1.0M in toluene, was placed in an additionfunnel and added to the cool reaction solution over about 20 minutes.The ice bath was then removed and the reaction mixture checked by tlcafter 30 minutes. If the reaction was not complete an additional 4.28 mlof the hydride solution was added. When reduction was complete, thereaction mixture was diluted with 26 ml of dry hexane and 4.32 g ofsodium fluoride powder was added with vigorous stirring. A 1.39 mlaliquot of water was then added with stirring. After an additional 30-40minutes had elapsed, during which stirring was continued, the reactionsolution was filtered through celite and rinsed with 100 ml methylenechloride. The solvent was then stripped off under vacuum and the residuefurther purified by silica gel column chromatography. The title compoundhas the following ¹ H NMR spectral data:

    ______________________________________                                        δ ppm                                                                   ______________________________________                                        7.28            2H, t, J = 7.5 Hz, H-19                                       6.86-6.98       3H, m, H-18, 20                                               5.46-5.83       2H, m, H-13-14                                                4.92            m, H-2' THP                                                   4.81            m, H-2' THP                                                   4.67            m, H-2' THP                                                   3.88            2H, m, H-6' THP                                               3.47            2H, m, H-6' THP                                               0.89            9H, s, t-butyl                                                0.5             s, silylmethyl                                                0.7             s, silylmethyl                                                 3.9-4.15       3H, m, H-11, 16                                               4.19            1H, m, H-9                                                    4.52            1H, m, H-15                                                   3.62            2H, m, H-6                                                    ______________________________________                                    

Proceeding in a similar manner, compounds made in Example 4 may betransformed to their corresponding alcohol.

EXAMPLE 6(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-2-ethan-1-ol

The following process is an alternative method for making the captionedalcohol.

A 1.08 g aliquot of(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)cyclopent-2α-yl)aceticacid was weighed into a round bottom flask equipped with a stirrer andseptum/N₂ /vacuum inlet. Dry tetrahydrofuran, 11 ml, was added todissolve the acetate. The flask was placed in a water bath at about18°-20° C. and purged five times with dry nitrogen. Then 0.392 ml ofborane methyl sulfide was added dropwise over 30 minutes. Stirring wasthen continued for about 3.5 hours. Methanol, 1 ml, was then addeddropwise, gas evolution being controlled by the rate of addition. Anadditional 5 ml of methanol was then added, the solution then beingstirred for another 30 minutes. The reaction mixture was thenconcentrated. The residue was dissolved in methanol and reconcentrated.The second concentrate was dissolved in 25 ml of diethyl ether andwashed with 1×5 ml of water, 1×5 ml of saturated aqueous sodiumbicarbonate, 1×5 ml of brine and dried over sodium sulfate. This driedsolution was filtered and concentrated, giving a colorless oil.

The oil from above was further purified by percolating it through acolumn of 10 g of silica gel packed wet in 10% ethyl acetate/hexane. Theproduct was eluted with successive portions of 200 ml 10% ethylacetate/hexane, 200 ml of 20% ethyl acetate/hexane and 200 ml of 30%ethyl acetate/hexane while collecting 20 ml fractions. Fractions 12-30were combined and the solvent removed in vacuo, giving the title productas a colorless oil.

EXAMPLE 7(1α-t-Butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde

A reaction flask was fitted with an addition funnel and dry nitrogeninlet/outlet valves. 150 ml of anhydrous methylene chloride and 5.96 gof anhydrous chromium (VI) trioxide was placed in the flask. The flaskwas vacuum purged with dry nitrogen and cooled in an ice bath toapproximately 15° C. To the flask was then added with vigorous stirring9.46 g of anhydrous pyridine after which the reaction mixture wasstirred vigorously under dry nitrogen at ambient temperature for 30minutes. Dry celite (5.0 g) was then added under nitrogen followed by4.7 g of(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)cyclopent-2α-yl)-2-ethan-1-olin 18.5 ml of anhydrous methylene chloride. The reaction solution wasstirred for 15-20 minutes, or until tlc indicated the reaction wascomplete, at which time 12.5 g of pulverized sodium hydrogen sulfatemonohydrate was added. After an additional 15 minutes of vigorousstirring, the reaction mixture was filtered and the retentate washedwith methylene chloride (3×50 ml). The combined methylene chloridesolutions were washed with 3×50 ml of water and the aqueous layer backextracted with 2×25 ml methylene chloride. The dried (anhydrous sodiumsulfate) methylene chloride solution was stripped under vacuum toprovide the title compound, having the following ¹ H NMR spectral data:

    ______________________________________                                        δ ppm                                                                   ______________________________________                                        7.28            2H, t, J = 7.5 Hz, H-19                                       6.86-6.98       3H, m, H-18, 20                                               5.46-5.73       2H, m, H-13-14                                                4.95            m, H-2' THP                                                   4.80            m, H-2' THP                                                   4.67            m, H-2' THP                                                   3.88            2H, m, H-6' THP                                               3.47            2H, m, H-6' THP                                               0.89            9H, s, t-butyl                                                0.5             s, silylmethyl                                                0.7             s, silylmethyl                                                 3.9-4.15       3H, m, H-11, 16                                               4.23            1H, m, H-9                                                    4.50            1H, m, H-15                                                   9.75            1H, m, H-6                                                    ______________________________________                                    

By this means, the compounds prepared in the Examples 5 and 6 areconverted to their corresponding acetaldehyde as illustrated by thefollowing compounds:

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-trifluoromethylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;and

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde.

EXAMPLE 8(1α-t-Butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde

Alternatively, the captioned aldehyde can be made directly from themethyl ester of Example 4 by means of the following reaction. A 100 mgaliquot ofmethyl-(1α-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)acetatewas weighed into a round bottom flask fitted with a stirrer andseptum/N₂ /vacuum inlet. Toluene, 1 ml, was added and the system vacuumpurged with N₂ five times. This solution was cooled in a dryice/isopropanol bath and 0.324 ml of 1M diisobutylaluminum hydride intoluene added was added dropwise over about 8 minutes. This solution wasstirred under nitrogen at -78° C. for 2 hours and then diluted with 10ml of diethyl ether. The cold bath was removed and 4 ml of saturatedaqueous ammonium chloride added, the resulting solution being stirredvigorously for 30 minutes and then filtered through celite. The aqueouslayer was extracted with diethyl ether, the extracts were combined,dried, and the solvent removed in vacuo to give the title compound as anoil.

This reaction may be used to convert any other methyl ester prepared inExample 4 to its corresponding aldehyde, as illustrated by the followingcompounds:

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-hexyloxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(l-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde;and

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehyde.

EXAMPLE 9(1α-t-Butyldimethylsiloxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)-1-but-3-yn-2-ol

To a reaction flask fitted with a pressure equalizing addition funneland dry nitrogen inlet/outlet valves was added 4.65 gm (7.9 mM) of(1α-t-butyldimethyl-silyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)acetaldehydein 30 ml of anhydrous methylene chloride. The flask was vacuum purgedwith dry nitrogen and cooled to approximately 15° C. while stirringvigorously. To this solution was added 9.0 ml of a 1.25M ethynylmagnesium chloride solution in tetrahydrofuran after which the pot wasstirred for 5-10 minutes at ambient temperature or until the reactionwas complete as indicated by tlc. Then 30 ml of methylene chloride and50 ml of warm (35° C.) filtered, saturated aqueous ammonium chloride wasadded and the solution stirred vigorously for 5-10 minutes. A 50 mlaliquot of warm water (35° C.) was added with an additional 5-10 minutestirring time. This solution was then filtered and the retentate washedwith 50 ml of methylene chloride and the aqueous layer extracted with 2additional 15 ml portions of methylene chloride. The combined methylenechloride extracts were mixed with 100 ml of water, the methylenechloride layer being removed and the aqueous layer back-extracted with20 ml of methylene chloride. The combined methylene chloride solutionswere dried over anhydrous sodium sulfate, filtered and the solventremoved under reduced pressure to afford the title compound as an oilyresidue.

The individual isomers may be separated as follows: the oil from abovewas chromatographed on a silica gel column made up in hexane, theproduct being eluted with 5%-15% ethyl acetate/hexane in 5% stepincrements of ethyl acetate concentration. This separation techniqueafforded two fractions, each comprising a stereochemically purepropargyl alcohol.

A ¹³ C NMR spectrum was measured for the purified, but unseparatedmixture of the two stereoisomers of(1α,4α-dihydroxy-3β-(3α-hydroxy-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-1-but-3-yn-2-oland for the two individual isomers after chromatographic separation. Theprotecting groups at C-9, C-11 and C-15 were hydrolyzed by acid beforemeasuring the NMR spectra. Acid hydrolysis was effected by acetic acidusing the conditions and reagents set out below in Example 17 though thereagents and conditions of Example 18 could also be used for thispurpose. The spectra were measured in CDCl₃ /CD₃ OD on a Bruker WM 300spectrometer operating at 75.473 MHz using a spectral width of 18,500Hz, 40° flip angles and 16K data tables, zero filled to 32K afterapplication of a 1.0 Hz line broadening giving a digital resolution inthe frequency domain of 0.03 ppm. Tetramethylsilane was used as theinternal standard for all spectra.

The resulting spectral data are set out in the following charts. Thechemical shift is given for each carbon in the formula. Numbers 1 to 16signify the particular carbon in question relative to formula I. Numbers17 to 20 signify the oxygen-substituted, ortho, meta and para carbonsrespectively of the phenoxy moiety. In this Example the first threecarbons are not present so there is no chemical shift recorded,dsignated by the letters NA for "not applicable." The separated isomersare designated "1" and "2" solely for the purpose of identification.

    ______________________________________                                        ISOMER MIXTURE                                                                1.    NA         6.    60.65, 61.37                                                                            11. 76.86, 76.95                             2.    NA         7.    34.28, 35.71                                                                            12. 55.47, 55.76                             3.    NA         8.    45.42, 47.33                                                                            13. 130.89                                   4.    72.68, 73.39                                                                             9.    71.84, 71.96                                                                            14. 134.86, 134.95                           5.    84.38, 85.17                                                                             10.   42.10, 42.19                                                                            15. 70.90, 70.97                             16.   71.65                                                                   17.   158.56                                                                  18.   114.75                                                                  19.   129.56                                                                  20.   121.20                                                                  ISOMER 1                                                                      1.    NA         6.    60.69     11. 77.03                                    2.    NA         7.    34.20     12. 55.64                                    3.    NA         8.    45.55     13. 130.70                                   4.    73.36      9.    71.89     14. 134.92                                   5.    84.27      10.   42.01     15. 70.92                                    16.   71.64                                                                   17.   158.54                                                                  18.   114.70                                                                  19.   129.56                                                                  20.   121.20                                                                  ISOMER 2                                                                      1.    NA         6.    61.36     11. 76.85                                    2.    NA         7.    35.71     12. 55.82                                    3.    NA         8.    47.43     13. 130.86                                   4.    72.54      9.    71.94     14. 134.86                                   5.    85.18      10.   42.10     15. 70.87                                    16.   71.66                                                                   17.   158.57                                                                  18.   114.75                                                                  19.   129.56                                                                  20.   121.21                                                                  ______________________________________                                    

By using the same reagents and conditions and repeating thechromatographic separation outlined here, the acetaldehydes prepared inExamples 7 and 8 are converted to the corresponding alcohol and may beseparated into the individual stereoisomers. The following list ofcompounds illustrates some of these compounds:

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-trifluoromethylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-tetrahydropyran-2-yloxy)-4-(m-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-1-but-3-yn-2-ol;

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-1-but-3-yn-2-ol;and

(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-but-3-yn-2-ol.

EXAMPLE 10Ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dienoate

A three necked flask was fitted with a nitrogen inlet needle, pressureequalized addition funnel and vacuum type distillation head fitted witha cold finger condenser. A solution of 3.18 g of one isomer of(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-1-but-3-yn-2-olin 18 ml of triethyl orthoacetate, to which was added 0.18 ml of glacialacetic acid, was introduced into the reaction vessel. Dry nitrogen wasbubbled through the reaction solution which was heated with stirring ina 170°-175° C. oil bath. Over a period of 30-35 minutes an additional0.1 ml of glacial acetic acid and 6.0 ml of triethyl orthoacetate wasadded to the reaction solution. A 6 ml volume of triethylorthoacetate-ethanol-acetic acid was distilled out of the reactionsystem after which the hot reaction solution was transferred to a secondflask and 12.0 ml of toluene added to the reaction solution. Thereagents were then distilled off under reduced pressure to give an oil.Toluene was added to this oil after which the toluene was removed underreduced pressure to afford the title compound having the following ¹ HNMR spectral data:

    ______________________________________                                        δ ppm                                                                   ______________________________________                                        7.28            2H, t, J = 7.5 Hz, H-19                                       6.86-6.98       3H, m, H-18, 20                                               5.43-5.82       2H, m, H-13-14                                                4.98            m, H-2' THP                                                   4.81            m, H-2' THP                                                   4.67            m, H-2' THP                                                   3.88            2H, m, H-6' THP                                               3.47            2H, m, H-6' THP                                               0.89            9H, s, t-butyl                                                0.5             s, silylmethyl                                                0.7             s, silylmethyl                                                 3.9-4.15       3H, m, H-11, 16                                               4.19            1H, m, H-9                                                    4.52            1H, m, H-15                                                   5.22            2H, m, H-4, 6                                                 4.13            2H, q J = 7.0, OCH.sub.2                                      3.01            2H, m, H-3                                                    1.27            2H, m, CH.sub.3                                               ______________________________________                                    

The crude allenyl ester was then chromatographed on silica gel elutingwith a gradient of hexane to 50% ethyl acetate/hexane to separate theallene from residual propargyl alcohol precursor.

Proceeding in the same manner, each of the individual isomers, or anunseparated mixture, of the compounds prepared in Example 7 and 8 arerearranged to their corresponding dienoate illustrated by the followingcompounds:

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-trifluoromethylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-tetrahydropyran-2-yloxy)-4-(m-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(o-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)1-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(m-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dienoate;

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-tetrahydropyran-2-yloxy)-4-(o-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dienoate;and

ethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-(p-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dienoate.

EXAMPLE 11(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dien-1-ol

To a three neck reaction flask fitted with a thermometer, pressureequalization addition funnel, dry nitrogen inlet and vacuum outlet wasadded 62.5 ml of absolute diethyl ether; the reaction system was thenpurged using dry nitrogen. There was then added, in portions, under adry nitrogen atmosphere with stirring, 0.32 g of powdered lithiumaluminum hydride. The solution was stirred for 15-20 minutes at ambienttemperature and then cooled to about 10° C. A solution of 6.56 g ofethyl-(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3β-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dienoatein 23.5 ml of absolute diethyl ether was added at a rate whichmaintained the temperature between 10°-15° C. The reaction mixture wasthen stirred at room temperature until the reduction was complete, thenagain cooled to about 10° C. and 3.0 ml of acetone added over about 15minutes after which the reaction pot was stirred for an additional 15minutes. There was then added dropwise 2.5 ml of saturated aqueouspotassium sodium tartrate. When there was no more evolution of hydrogengas, an additional 29.0 ml of saturated aqueous sodium potassiumtartrate was added, the reaction pot being at ambient temperature. Theaqueous phase was recovered and extracted with 2×25 ml of ethyl acetate.The combined ethereal and ethyl acetate extracts were washed with 35 mlof water. The organic layer was then dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give the title alcoholhaving the following ¹ H NMR spectral data:

    ______________________________________                                        δ ppm                                                                   ______________________________________                                        7.28            2H, t, J = 7.5 Hz, H-19                                       6.86-6.98       3H, m, H-18, 2O                                               5.46-5.83       2H, m, H-13-14                                                4.96            m, H-2' THP                                                   4.82            m, H-2' THP                                                   4.67            m, H-2' THP                                                   3.88            2H, m, H-6' THP                                               3.47            2H, m, H-6' THP                                               0.89            9H, s, t-butyl                                                0.5             s, silylmethyl                                                0.7             s, silylmethyl                                                 3.9-4.15       3H, m, H-11, 16                                               4.19            1H, m, H-9                                                    4.52            1H, m, H-15                                                   3.67            2H, t, J = 6, H-2                                             5.08            1H, m, H-4                                                    5.10            1H, m, H-6                                                    ______________________________________                                    

These same reagents and conditions will reduce any of the dienoatecompounds prepared in Example 10 above to the corresponding alcohol.

EXAMPLE 12(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-(1-methansulfonyloxy)-hexa-3,4-diene

To a reaction flask fitted with nitrogen inlet/outlet valves andmechanical stirrer was added 7.24 g of(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dien-1-olin 67 ml of anhydrous methylene chloride. To this was added 6.7 ml ofanhydrous triethylamine at which time the system was purged with drynitrogen and cooled to about -30° C. There was then added 2.35 g ofmethanesulfonyl chloride in 13.5 ml of anhydrous methylene chloride overa 15-20 minute period while maintaining the reaction solution at itsinitial temperature. The reaction mixture was then stirred until thereaction was complete, about 30 minutes. The cooling bath was removedand a solution of 2.0 ml of triethylamine in 20 ml of methylene chloridewas added followed by 20 ml of saturated, aqueous sodium bicarbonate.The methylene chloride layer was recovered and the aqueous layerextracted with 2×50 ml of methylene chloride. The combined methylenechloride extracts were washed with 20 ml of saturated sodiumbicarbonate-water (1:1-V:V). The organic layer was dried over anhydroussodium sulfate and solvents removed under reduced pressure to yield thetitle compound having the following ¹ H NMR spectral data:

    ______________________________________                                        δ ppm                                                                   ______________________________________                                        7.28            2H, t, J = 7.5 Hz, H-19                                       6.86-6.98       3H, m, H-18, 20                                               5.46-5.83       2H, m, H-13-14                                                4.96            m, H-2' THP                                                   4.81            m, H-2' THP                                                   4.67            m, H-2' THP                                                   3.88            2H, m, H-6' THP                                               3.47            2H, m, H-6' THP                                               0.89            9H, s, t-butyl                                                0.5             s, silylmethyl                                                0.7             s, silylmethyl                                                 3.9-4.15       3H, m, H-11, 16                                               4.19            1H, m, H-9                                                    4.52            1H, m, H-15                                                   4.23            2H, t, J = 6, H-2                                             5.04            1H, m, H-4                                                    5.13            1H, m, H-6                                                    2.98            3H, s, SO.sub.3 Me                                            ______________________________________                                    

Proceeding in this manner, any of the other dienols prepared by themethod of Example 11 may be converted to their corresponding mesylates.

EXAMPLE 13(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile

To a flask fitted with dry nitrogen inlet/outlet valves was added 4.7 gof potassium cyanide and 16.5 ml of anhydrous dimethylsulfoxide. Thismixture was stirred under dry nitrogen at 75°-80° C. for about 30minutes. There was then added, in one portion, a solution of 8.13 g of(1α-t-butyldimethylsilyloxy-4α-(tetrahydropyran-2-yloxy)-3.beta.-(3α-(tetrahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-(1-methanesulfonyloxy)-hexa-3,4-dienein 20 ml of anhydrous dimethylsulfoxide. The reaction was continued forabout 60 minutes in the 60°-80° C. bath in order to effect completion ofthe reaction. The reaction solution was then cooled to about 40° C. and5 ml of methylene chloride added. This mixture was then further cooledto ambient temperature and transferred to a separatory funnel containing120 ml of methylene chloride. The reaction flask was washed withmethylene chloride, the washes being transferred to the extractionfunnel. The methylene chloride solution of crude nitrile was shaken with160 ml of water whereupon the upper aqueous phase was recovered andextracted with 3×40 ml of methylene chloride. The combined methylenechloride extracts were washed with 120 ml of water. The combined aqueousphases were then again extracted with 40 ml of methylene chloride. Allmethylene chloride extracts were combined and dried over anhydroussodium sulfate, filtered, and the solvent removed under reduced pressureto yield the captioned compound. The crude nitrile was further purifiedby passing the crude oil through a silica gel column, eluting with ahexane/50% ethyl acetate-hexane gradient to give fractions of thecaptioned compound having the following ¹ H NMR spectral data:

    ______________________________________                                        δ ppm                                                                   ______________________________________                                        7.28            2H, t, J = 7.5 Hz, H-19                                       6.86-6.98       3H, m, H-18, 20                                               5.46-5.83       2H, m, H-13-14                                                4.96            m, H-2' THP                                                   4.82            m, H-2' THP                                                   4.67            m, H-2' THP                                                   3.88            2H, m, H-6' THP                                               3.47            2H, m, H-6' THP                                               0.89            9H, s, t-butyl                                                0.5             s, silylmethyl                                                0.7             s, silylmethyl                                                3.9-4.15        3H, m, H-11, 16                                               4.19            1H, m, H-9                                                    4.52            1H, m, H-15                                                   ______________________________________                                    

The other mesylates, or a similiar sulfonyl ester, prepared in Example12 may be converted to their corresponding nitrile by the foregoingmethod as illustrated by the following compounds:

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(m-trifluoromethylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(m-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(o-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(p-fluorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(p-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(o-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(m-chlorophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(m-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(o-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(p-bromophenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(p-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(o-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(m-methylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(m-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(o-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(p-methoxyphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(p-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(o-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-B6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(m-hexylphenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(m-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-tetrahydropyran-2-yloxy)-4-(o-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;and

(1α-t-butyldimethylsilyloxy-4α-(tetrapyran-2-yloxy)-3β-(3.alpha.-(tetrahydropyran-2-yloxy)-4-(p-hexyloxy-phenoxy)-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile.

EXAMPLE 14 Methyl9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate

A reaction flask fitted with a condenser and nitrogen inlet/outletvalves was charged with 3.47 g of the 1-nitrile from Example 13dissolved in 37.0 ml of 2-methoxyethanol. To this was added a solutionof 0.9 g of potassium hydroxide in 3.1 ml of water after which thesystem was vacuum purged with dry nitrogen. The reaction was then heatedat reflux under nitrogen for approximately 63 hours. The reactionmixture was then cooled to about 50°-60° C. and the solvents removedunder reduced pressure. The residue was dissolved in 5.0 ml of water andtransferred to a reaction flask equipped with a pressure equalizationaddition funnel and pH electrode. The solution was cooled to between5°-10° C. and cool (10° C.) aqueous hydrochloric acid (1 part conc. HClto 2 parts water) was added until the pH of the solution wasapproximately 2. Ethyl acetate/diethyl ether (1:1), 20 ml, was added andthe system stirred at ambient temperature. The aqueous phase wasrecovered and extracted with additional 2×20 ml aliquots of ethylacetate/diethyl ether (1:1). The combined organic layers were washedwith 2×5 ml of water, dried over anhydrous sodium sulfate and filtered.Solvent was removed under reduced pressure to yield a crude residue ofthe title acid.

At this point the acid may be recovered and purified by conventionalmeans such as by extraction, chromatography and the like. The acid hasthe following ¹ H NMR spectral data:

    ______________________________________                                        δ ppm                                                                   ______________________________________                                        7.28            2H, t, J = 7.5 Hz, H-19                                       6.86-6.98       3H, m, H-18, 20                                               5.46-5.87       2H, m, H-13-14                                                4.95            m, H-2' THP                                                   4.85            m, H-2' THP                                                   4.67            m, H-2' THP                                                   3.88            2H, m, H-6' THP                                               3.47            2H, m, H-6' THP                                               3.9-4.15        3H, m, H-11, 16                                               4.19            1H, m, H-9                                                    4.52            1H, m, H-15                                                   ______________________________________                                    

Alternatively, however, without further purification the crude acid wastransferred to a reaction flask in 45 ml of dimethylformamide. To thissolution was added 1.65 g of powdered sodium bicarbonate followed by 2.9ml of methyl iodide.

This solution was stirred at 45° C. for 48 hours or until esterificationwas completed. The reaction mixture was filtered through celite. Thefilter cake was washed with 50 ml of methylene chloride and the combinedorganic solvents were evaporated under reduced pressure to afford anoily residue. This residue was taken up in 65 ml of methylene chloridewhich was washed with 2×15 ml of water. The aqueous layer wasback-extracted with methylene chloride which was combined with the othermethylene chloride solution, dried over anhydrous sodium sulfate andfiltered. Removal of the solvent afforded a crude methyl ester which wasfurther purified chromatographically on silica gel. Chromatographicpurification was effected using a hexane/50% ethyl acetate-hexanegradient, 75% ethyl acetate-hexane and finally ethyl acetate, as needed.Fractions containing the pure methyl ester were combined and the solventremoved under reduced pressure to give the title compound having thefollowing ¹ H NMR spectral data:

    ______________________________________                                        δ ppm                                                                   ______________________________________                                        7.28            2H, t, J = 7.5 Hz, H-19                                       6.86-6.98       3H, m, H-18, 20                                               5.46-5.83       2H, m, H-13-14                                                4.96            m, H-2' THP                                                   4.79            m, H-2' THP                                                   4.70            m, H-2' THP                                                   3.88            2H, m, H-6' THP                                               3.47            2H, m, H-6' THP                                               3.9-4.15        3H, m, H-11, 16                                               4.23            1H, m, H-9                                                    4.52            1H, m, H-15                                                   3.67            3H, s, OMe                                                    ______________________________________                                    

This procedure will also serve to convert the other nitrile compoundsprepared in Example 13 to their corresponding 9-hydroxy-dienoic methylesters, illustrated by the following compounds:

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-trifluoromethylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-hexylphenoxy-7,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-hexylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-hexylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-hexyloxyphenoxy-17,18,19,20-tetranorprosta-1(E)-buten-1-yl)-cyclopent-2α-yl)-6-hexa-3,4-dieno-1-nitrile;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-hexyloxyphenoxy-17,18,19,20-tetraorprosta-4,5,13(E)-trienoate;

methyl9α-hydroxy-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-hexyloxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(e)-trienoate;

9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid;

9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-o-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid;

9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-p-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid;

9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-m-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid;

9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-m-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid;

9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-p-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid;

9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-p-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid;

9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-o-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid; and

9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-p-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid.

EXAMPLE 15 Methyl9α-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate

To a suspension of chromium trioxide (2.66 g) in methylene chloride (100ml) cooled to about -20° C. was added solid 3,5-dimethylpyrazole (2.58g) under dry nitrogen. After stirring for approximately 1/2 hour at -20°C., 3.37 g of methyl9α-hydroxy-11α,15α-bis(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoatedissolved in 50 ml of methylene chloride was added. Stirring wascontinued at the reduced temperature for approximately 1 hour. Silicagel (50 g) was then added and the solvent removed under reducedpressure. The impregnated silica gel was charged onto the top of asilica gel column made up in hexane. Recovery and separation of thetitle compound was effected by a 5%-50% gradient of ethyl acetate inhexane. Combined appropriate fractions were concentrated under reducedpressure to give the title compound having the following ¹ H NMRspectral data:

    ______________________________________                                        δ ppm                                                                   ______________________________________                                        7.28            2H, t, J = 7.5 Hz, H-19                                       6.86-6.98       3H, m, H-18, 20                                               5.48-5.95       2H, m, H-13-14                                                4.96            m, H-2' THP                                                   4.82            m, H-2' THP                                                   4.67            m, H-2' THP                                                   3.88            2H, m, H-6' THP                                               3.50            2H, m, H-6' THP                                               3.9-4.15        3H, m, H-11, 16                                               4.19            1H, m, H-9                                                    4.56            1H, m, H-15                                                   3.66            3H, s, OMe                                                    ______________________________________                                    

Proceeding in a similar manner, but substituting the appropriate methylester or free acid prepared in Example 14 for the 16-phenoxy-substitutedcompound herein above, all compounds prepared in Example 14 areconverted to their corresponding C-9 oxo compound as illustrated by thefollowing compounds:

methyl9-oxo-11α,15α-bis(tetrapyran-2-yloxy)-16-m-trifluoromethylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-methylphenoxy-7,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-hexylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-hexylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-hexylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-hexyloxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-hexyloxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-hexyloxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(e)-trienoate;

9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-o-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-p-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-m-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-m-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-p-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-p-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-o-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;and

9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-p-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate.

EXAMPLE 16Methyl-9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate

A 0.3 mg aliquot of9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoicacid was dissolved in 10 ml of anhydrous diethyl ether to which wasadded an excess of diazomethane at room temperature. The reaction wasfollowed by tlc and when complete, the ether and excess diazomethane wasremoved under vacuum to give the title methyl ester.

Proceeding in the same manner, all the 9-oxo acid compounds prepared inExample 15 are converted to their corresponding methyl ester asillustrated by the following compounds:

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-trifluoromethylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl-9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-methylphenoxy-17,18,19,20-tetraorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-m-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-o-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;and

methyl9-oxo-11α,15α-bis-(tetrapyran-2-yloxy)-16-p-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate.

EXAMPLE 17 Methyl9-oxo-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate

A 0.3 mg aliquot of the protected methyl ester of Example 15 wasdissolved in a solution of glacial acetic acid (10.0 ml), water (6.0 ml)and tetrahydrofuran (1.7 ml). This reaction mixture was stirred for 12hours at about 40° C. under dry nitrogen. The solvents were removedunder reduced pressure. The resulting residue was subjected toazeotropic distillation with toluene (3×10 ml). Further purification waseffected on a silica gel column made up in hexane, the product beingeluted with 75% ethyl acetate in hexane. Appropriate fractions werecombined and evaporated to dryness under reduced pressure to give thetitle compound.

Proceeding in a similar manner, the esters prepared in Examples 15 and16 are converted to their corresponding dihydroxy compound asillustrated by the following compounds:

methyl9-oxo-11α,15α-dihydroxy-16-m-trifluoromethylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy16-m-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-o-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-p-fluorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-p-chlorophenoxy-17,18,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-o-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-m-chlorophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-m-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-o-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-p-bromophenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-p-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-o-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16m-methylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-m-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-o-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-p-methoxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-p-hexylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-o-hexylphenoxy-17,18,9,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-m-hexylphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy-16-m-hexyloxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;

methyl9-oxo-11α,15α-dihydroxy)-16-o-hexyloxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate;and

methyl9-oxo-11α,15α-dihydroxy)-16-p-hexyloxyphenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate.

This procedure may also be used to hydrolytically cleave the ethergroups of any of the intermediates set out herein in the foregoingExamples.

EXAMPLE 18 Methyl9-oxo-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate

A 500 mg aliquot of the protected methyl ester prepared in Example 15was dissolved in methylene chloride and 0.1 ml of 48% hydrofluoric acidadded with vigorous stirring. There was then added dropwise, 7.5 ml of amethylene chloride solution of mercaptoethanol (17 mg/ml) over 30minutes. The solution was then neutralized with approximately 0.3 ml ofaqueous sodium bicarbonate. Methylene chloride was used to extract theproduct. The combined extracts were dried with sodium sulfate, thesolvent removed uner reduced pressure and the product purified using asilica gel column. The column was eluted in steps with 20% ethylacetate/hexane, 50% and 75% ethyl acetate/hexane and finally ethylacetate. As in Example 17, all alkyl ester compounds prepared inExamples 15 and 16 may be hydrolyzed by the foregoing procedure.

Individual alkyl 9-oxo-11α,15α-dihydroxy-16-phenoxy-trienoate isomerswere prepared by taking a single propargyl alcohol isomer as prepared inExample 9 and carrying that single isomer through the subsequent stepsas set out in Examples 10-18

As in Example 9, ¹³ C NMR spectra were measured on a mixture and on theindividual allene isomers. The spectra were obtained in the same mannerand under the same conditions as set out in Example 9 except that CD₃ ODwas not added to solubilize the compound in CDCl₃. The spectral datahere are numbered the same as in Example 9. The allenic isomerdesignated "R" here was derived from isomer "1" of Example 9 and theallenic isomer "S" was derived from isomer "2" of Example. The spectraldata are as follows:

    ______________________________________                                        MIXTURE OF ISOMERS                                                            1.   173.59     6.     88.76     11. 71.97, 72.01                             2.   33.08, 33.24                                                                             7.     26.73     12. 54.14, 54.19                             3.   23.71, 23.83                                                                             8.     53.34, 53.48                                                                            13. 131.91                                   4.   90.26, 90.40                                                                             9.     213.63, 213.40                                                                          14. 133.23, 133.34                           5.   204.79     10.    45.99     15. 70.80                                    16.  71.57                                                                    17.  158.39                                                                   18.  114.65                                                                   19.  129.64                                                                   20.  121.43                                                                   OMe  51.65                                                                    1.   173.58     6.     88.77     11. 71.94                                    2.   33.08      7.     26.70     12. 54.13                                    3.   23.70      8.     53.43     13. 131.90                                   4.   90.37      9.     213.62    14. 133.49                                   5.   204.75     10.    45.94     15. 70.86                                    16.  71.54                                                                    17.  158.39                                                                   18.  114.63                                                                   19.  129.62                                                                   20.  121.40                                                                   OMe  51.63                                                                    THE "S" ALLENIC ISOMER                                                        1.   173.53     6.     88.74     11. 71.98                                    2.   33.24      7.     26.75     12. 54.19                                    3.   23.83      8.     53.46     13. 131.91                                   4.   90.26      9.     213.62    14. 133.23                                   5.   204.71     10.    46.02     15. 70.79                                    16.  71.58                                                                    17.  158.39                                                                   18.  114.65                                                                   19.  129.63                                                                   20.  121.42                                                                   OMe  51.65                                                                    ______________________________________                                    

EXAMPLE 19 Crystalline (4,5,6R,8R)methyl9-oxo-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate

Approximately 720 mg of (4,5,6R,8R)-methyl9-oxo-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoateas an oil was stored in a freezer where the oily material spontaneouslycrystallized. A sample (50 mg) of the solid material was purified byflash chromatography, then crystallized from ethyl acetate/hexane togive needle shaped crystals with a melting point of 71°-71.5° C. Thematerial was determined 98% pure by HPLC.

EXAMPLE 20 Biological activity of (4,5,6R,8R) methyl9-oxo-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate(Histamine Induced Gastric Acid Secretion Assay)

Spraque-Dawley (Hilltop) male rats were used in the assay. Animals had acircular plastic collar fastened around their necks in order to preventaccess to food or feces and assure gastric emptying during a 48 hourstarvation period. The title compound was administered orally by gavageduring the morning of the experiment, 30 minutes prior to surgery.During this procedure animals were ether anesthetized and one ligaturewas placed on the duodenum adjacent to the pyloric sphincter and anotheror the esophagus posterior to the larynx. The laparotomy was closed withwound clips and 40 mg/kg histamine diphosphate was injected oncesubcutaneously during a 3 hour study interval of stimulated gastric acidsecretion. At the end of the 3 hours rats were sacrificed, gastric juicecontent of the stomach aspirated, and its volume recorded. An aliquot ofthe juice was titrated with 0.02N NaOH to pH=7.0±0.1 end point on a pHmeter. Gastric acid secreted was calculated as milli-equivalents per 100g body weight. Treated groups were compared statistically to control. Inthis test, (4,5,6R,8R)methyl9-oxo-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate,given at doses of from 0.5 to 4 μg/kg, was found to have an extrapolatedED₅₀ of 6 μg/kg.

EXAMPLE 21 Toxicity of (4,5,6R,8R)methyl9-oxo-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoate

(4,5,6R,8R)methyl9-oxo-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoatewas given to male (Sim (ICR) FBR) mice intraperitoneally at doses from0.125-0.5 mg/Kg. No deaths were noted at the doses given.

What is claimed is:
 1. A process for preparing a compound of the formula##STR8## or its counterpart of the unnatural prostaglandinconfiguration, or mixtures thereof, wherein R is hydrogen or a loweralkyl, preferably methyl; X is hydrogen, halo, trifluoromethyl, loweralkyl or lower alkoxy, preferably hydrogen, and the wavy lines representthe α or β configuration with the proviso that when one wavy line is αthe other is β, or a pharmaceutically acceptable, non-toxic salt of thecompound of formula I wherein R is hydrogen, which process compriseshydrolyzing with acid the R¹ groups of a compound of the formula##STR9## or its counterpart of the unnatural prostaglandinconfiguration, or mixtures thereof, wherein R, X and the wavy lines areas defined above and R¹ is a base-stabile acid-labile ether-forminggroup, preferably tetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethylmost preferably tetrahydropyranyl, and optionally converting thecompound of formula I wherein R is hydrogen to its pharmaceuticallyacceptable, non-toxic salts.
 2. The process of claim 1 wherein said acidis an alkanoic acid of 1 to 6 carbons, preferably 2 to 4 carbon atoms,most preferably acetic acid.
 3. The process of claim 2 wherein saidacetic acid comprises 85-95 w/v% of 20-60 w/v% aqueous glacial aceticacid with 5-15 w/v% of an organic solvent.
 4. The process of claim 3wherein said aqueous acid comprises 60 w/v% water, 30 w/v% acetic acid,and 10 w/v% tetrahydrofuran, and the reaction being carried out at atemperature between 20° to 60° C. under nitrogen.
 5. The process ofclaims 1-4 wherein the starting compound is the (4,5,6)R,8R-stereoisomer, or the (4,5,6)S, 8R-stereoisomer.
 6. The process ofclaim 1 wherein said acid is a hydrogen halide, preferably hydrogenfluoride.
 7. The process of claim 6 wherein said hydrolysis is effectedby at least 2.05 to 10 equivalents of an aqueous solution of the acid,preferably 2.05 to 3 equivalents of hydrogen fluoride, dispersed in awater immiscible solvent, preferably a halogenated hydrocarbon,containing 2.0 to 3.0 equivalents of a mercaptan, the reaction beingeffected at a temperature between -30° to 50° C., preferably between10°-50° C.
 8. The process of claim 7 wherein said acid comprises 2.5equivalents of aqueous hydrogen fluoride, the solvent is methylenechloride, the mercaptan is mercaptoethanol in an amount of 2.0equivalents, and the reaction is effected at ambient temperature.
 9. Theprocess of claims 6-8 wherein the starting compound is the (4,5,6)R,8R-stereoisomer, or the (4,5,6)S, 8R-stereoisomer.
 10. The process ofclaim 1 wherein the compound of formula II or its counterpart of theunnatural prostaglandin configuration, or mixtures thereof, is made byoxidizing a compound of the formula ##STR10## or its counterpart of theunnatural prostaglandin configuration, or mixtures thereof, wherein R,R¹, X and the wavy lines are as defined in claim
 1. 11. The process ofclaim 10 wherein the oxidization is effected by a mild oxidant,preferably a chromium derived oxidant, most preferably chromium trioxidein the presence of 3,5-dimethylpyrazole, or Collins reagent (chromiumtrioxide and pyridine).
 12. The process of claims 10-11 wherein thestarting compound is the (4,5,6)R, 8R-stereoisomer or the (4,5,6)S,8R-stereoisomer.
 13. The process of claim 1 wherein the compound offormula II with R being a lower alkyl, or its counterpart of theunnatural prostaglandin configuration, or mixtures thereof, is formed byesterifying, preferably with a lower diazoalkane, most preferablydiazomethane, the acid function of a compound of the formula ##STR11##or its counterpart of the unnatural prostaglandin configuration, ormixtures thereof, wherein X, R¹ and the wavy lines are as defined inclaim
 1. 14. A process for preparing a compound of the formula ##STR12##or its counterpart of the unnatural prostaglandin configuration, ormixtures thereof, with R being a lower alkyl, preferably methyl; X ishydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, and thewavy lines represent the α or β configuration with the proviso that whenone wavy line is α the other is β, which process comprises esterifyingwith a lower diazoalkane, preferably diazomethane, the acid of acompound of the formula ##STR13## or its counterpart of the unnaturalprostaglandin configuration, or mixtures thereof, wherein X and the wavylines are as defined above.
 15. A compound of the formula ##STR14## orits counterpart of the unnatural prostaglandin configuration, ormixtures thereof, wherein R is hydrogen or a lower alkyl preferablymethyl; R¹ is a base-stabile acid-labile ether-forming group preferablytetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl, most preferablytetrahydropyranyl; X is hydrogen, halo, trifluoromethyl, lower alkyl orlower alkoxy, preferably hydrogen, and the wavy lines represent the α orβ configuration with the proviso that when one wavy line is α the otheris β.
 16. The compound of claim 15 which is the (4,5,6)R,8R-stereoisomer or the (4,5,6)S, 8R-stereoisomer.
 17. A compound of theformula ##STR15## or its counterpart of the unnatural prostaglandinconfiguration, or mixtures thereof, wherein R is hydrogen or a loweralkyl, preferably methyl; R¹ is a base-stabile acid-labile ether-forminggroup, preferably tetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl,most preferably tetrahydropyranyl; X is hydrogen, halo, trifluoromethyl,lower alkyl or lower alkoxy, preferably hydrogen, and the wavy linesrepresent the α or β configuration with the proviso that when one wavyline is α the other is β.
 18. The compound of claim 17 which is the(4,5,6)R, 8R-stereoisomer or the (4,5,6)S, 8R-stereoisomer.
 19. Aprocess for preparing a compound of the formula ##STR16## or itscounterpart of the unnatural prostaglandin configuration, or mixturesthereof, wherein M is hydrogen or an alkali metal, R¹ is a base-stabileacid-labile ether-forming group; X is hydrogen, halo, trifluoromethyl,lower alkyl or lower alkoxy, and the wavy lines represent the α or βconfiguration with the proviso that when one wavy line is α the other isβ, which process comprises homologating a compound of the formula##STR17## or its counterpart of the unnatural prostaglandinconfiguration, or mixtures thereof, wherein X, R¹ and the wavy lines areas defined above, R² is a base-labile ether-forming group and R is analkyl of 1-6 carbon atoms, and optionally acidifying a compound offormula IV wherein M is an alkali metal to its corresponding free acid.20. A process for preparing a compound of the formula ##STR18## or itscounterpart of the unnatural prostaglandin configuration, or mixturesthereof, wherein M is hydrogen or an alkali metal salt, R¹ is abase-stabile acid-labile ether-forming group, preferablytetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl, most preferablytetrahydropyranyl; X is hydrogen, halo, trifluoromethyl, lower alkyl orlower alkoxy, preferably hydrogen, and the wavy lines represent the α orβ configuration with the proviso that when one wavy line is α the otheris β, which process comprises hydrolyzing with base preferably a strongbase most preferably sodium or potassium hydroxide, a compound of theformula ##STR19## or its counterpart of the unnatural prostaglandinconfiguration, or mixtures thereof, wherein R² is a base-labileether-forming group, preferably --SiR₄ R₅ R₆ wherein R₄, R₅ and R₆ arethe same or different and are alkyl of 1-6 carbon atoms, phenyl orarylalkyl, such as phenylalkyl, alkyl-substituted-phenylalkyl ornaphthylalkyl except that all three may not be simultaneously methyl,most preferably t-butyldimethylsilyl; R¹, X and the wavy lines are asdefined above, and optionally acidifying a compound of formula IVwherein M is an alkali metal to its corresponding free acid.
 21. Theprocess of claim 20 wherein the starting compound is the (4,5,6)R,8R-stereoisomer or the (4,5,6)S, 8R-stereoisomer.
 22. A compound of theformula ##STR20## or its counterpart of the unnatural prostaglandinconfiguration, or mixtures thereof, wherein R¹ is a base-stabileacid-labile ether-forming group, preferably tetrahydropyranyl,tetrahydrofuranyl or 2-ethoxyethyl, most preferably tetrahydropyranyl;R² is a base-labile ether-forming group, preferably --SiR₄ R₅ R₆ whereinR₄, R₅ and R₆ are the same or different and are alkyl of 1-6 carbonatoms, phenyl or arylalkyl, such as phenylalkyl,alkyl-substituted-phenylalkyl, or naphthylalkyl except that all threemay not be simultaneously methyl, most preferably t-butyldimethylsilyl;X is hydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy,preferably hydrogen, and the wavy lines represent the α or βconfiguration with the proviso that when one wavy line is α the other isβ.
 23. The compound of claim 22 which is the (4,5,6)R, 8R-stereoisomeror the (4,5,6)S, 8R-stereoisomer.
 24. A process for preparing a compoundof the formula ##STR21## or its counterpart of the unnaturalprostaglandin configuration, or mixtures thereof, wherein R¹ is abase-stabile acid-labile ether-forming group, preferablytetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl most preferablytetrahydropyranyl; R² is a base-labile ether-forming group, preferably--SiR₄ R₅ R₆ wherein R₄, R₅ and R₆ are the same or different and arealkyl of 1-6 carbon atoms, phenyl or arylalkyl such as phenylalkylalkyl-substituted-phenylalkyl or naphthylalkyl except that all three maynot be simultaneously methyl, most preferably t-butyldimethylsilyl; X ishydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy preferablyhydrogen and the wavy lines represent the α or β configuration with theproviso that when one wavy line is α the other is β, which processcomprises reacting an alkali metal cyanide preferably sodium orpotassium cyanide with a compound of the formula ##STR22## or itscounterpart of the unnatural prostaglandin configuration, or mixturesthereof, wherein Y is a halogen or --SO₂ R³, preferably --SO₂ R³ and R³is lower alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, aryl(6-10C) lower alkyl or substituted aryl (6-10C) lower alkyl, mostpreferably methyl or p-tolyl; R¹, R², X and the wavy lines are definedabove.
 25. The process of claim 24 wherein the starting compound is the(4,5,6)R, 8R-stereoisomer or the (4,5,6)S, 8R-stereoisomer.
 26. Acompound of the formula ##STR23## or its counterpart of the unnaturalprostaglandin configuration, or mixtures thereof, wherein Y is a leavinggroup such as a halogen or --SO₂ R³ with R³ being lower alkyl of 1-6carbon atoms, aryl of 6-10 carbon atoms, aryl (6-10C) lower alkyl orsubstituted aryl (6-10C) lower alkyl, preferably methanesulfonyl orp-toluenesulfonyl, R¹ is a base-stabile acid-labile ether-forming group,preferably tetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl, mostpreferably tetrahydropyranyl; R² is a base-labile ether-forming group,preferably --SiR₄ R₅ R⁶ wherein R₄, R₅ and R₆ are the same or differentand are alkyl of 1-6 carbon atoms, phenyl or arylalkyl such asphenylalkyl, alkyl-substituted-phenylalkyl or naphthylalkyl except thatall three may not be simultaneously methyl, most preferablyt-butyldimethyl; X is hydrogen, halo, trifluoromethyl, lower alkyl orlower alkoxy, preferably hydrogen, and the wavy lines represent the α orβ configuration with the proviso that when one wavy line is α the otheris β.
 27. The compound of claim 26 which is the (4,5,6)R,8R-stereoisomer or the (4,5,6)S, 8R-stereoisomer.
 28. A process formaking a compound of the formula ##STR24## or its counterpart of theunnatural prostaglandin configuration, or mixtures thereof, wherein R islower alkyl; R¹ is a base-stabile, acid labile ether forming group,preferably tetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl, mostpreferably tetrahydropyranyl; R² is a base-labile ether forming group,preferably --SiR₄ R₅ R₆ wherein R₄, R₅ and R₆ are the same or differentand are alkyl of 1-6 carbon atoms, phenyl or arylalkyl such asphenylalkyl, alkyl-substituted-phenylalkyl or naphthylalkyl except thatall three may not be simultaneously methyl, most preferablyt-butyldimethylsilyl; X is hydrogen, halo, trifluoromethyl, lower alkylor lower alkoxy, preferably hydrogen, and the wavy lines represent the αor β configuration with the proviso that when one wavy line is α theother is β, which process comprises reacting a propargyl alcohol of thefollowing formula ##STR25## or its counterpart of the unnaturalprostaglandin configuration, or mixtures thereof, wherein R¹, R², X andthe wavy lines are defined above, with a lower alkyl orthoacetate and acatalytic amount of a lower alkanoic acid.
 29. The process of claim 28wherein the trialkyl orthoacetate is triethyl orthoacetate and thealkanoic acid of 1-6 carbon atoms, preferably acetic acid or propionicacid in a quantity of 0.1-5% by volume relative to the volume oftriethyl orthoacetate and the process is carried out at an elevatedtemperature preferably at a temperature of between 100°-130° C.
 30. Acompound of the formula ##STR26## or its counterpart of the unnaturalprostaglandin configuration, or mixtures thereof, wherein R is loweralkyl; R¹ is a base-stabile ether forming group preferablytetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl, most preferablytetrahydropyranyl; R² is a base-labile ether forming group, preferably--SiR₄ R₅ R₆ wherein R₄, R₅ and R₆ are the same or different and arealkyl of 1-6 carbon atoms, phenyl or arylalkyl such as phenylalkyl,alkyl-substituted-phenylalkyl or naphthylalkyl except that all three maynot be simultaneously methyl, most preferably t-butyldimethylsilyl; X ishydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, preferablyhydrogen, and the wavy lines represent the α or β configuration with theproviso that when one wavy line is α the other is β.
 31. The compound ofclaim 30 which is the (4,5,6)R, 8R-stereoisomer or the (4,5,6)S,8R-stereoisomer.
 32. A compound of the formula ##STR27## or itscounterpart of the unnatural prostaglandin configuration, or mixturesthereof, wherein R¹ is a base-stabile ether-forming group, preferablytetrahydropyranyl, tetrafuranyl or 2-ethoxyethyl, most preferablytetrahydropyranyl; R² is a base-labile ether-forming group, preferably--SiR₄ R₅ R₆ wherein R₄, R₅ and R₆ are the same or different and arealkyl of 1-6 carbon atoms, phenyl or arylalkyl such as phenylalkyl,alkyl-substituted-phenylalkyl or naphthylalkyl except that all three maynot be simultaneously methyl, most preferably t-butyldimethylsilyl; X ishydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, preferablyhydrogen, and the wavy lines represent the α or β configuration with theproviso that when one wavy line is α the other is β.
 33. The compound ofclaim 32 which is the 6R, 8R-stereoisomer or the 6S, 8R-stereoisomer.34. A process for preparing a compound of the formula ##STR28## or itscounterpart of the unnatural prostaglandin configuration, or mixturesthereof, wherein R¹ is a base-stabile, acid-labile ether-forming group;R² is a base-labile ether-forming group; X is hydrogen, halo,trifluoromethyl, lower alkyl or lower alkoxy, and the wavy linesrepresent the α or β configuration with the proviso that when one wavyline is α the other is β, which process comprises treating with a metalacetylide in an inert solvent a compound of the formula ##STR29## or aracemic or non-racemic mixture thereof, wherein R¹, R² and X are definedabove, and optionally separating the diastereomers of formula VIII bychromatography.
 35. The process of claim 34 wherein the metal acetylideis ethynyl magnesium chloride, ethynyl magnesium bromide, ethynylmagnesium iodide, ethynyl lithium or lithium acetylide ethylene diaminecomplex, the reaction being carried out in a halogenated lower alkane,preferably methylene chloride, an ether or toluene at a temperaturebetween 0°-50° C., preferably 20°-30° C.
 36. A compound of the formula##STR30## or a racemic or non-racemic mixture thereof wherein R¹ is or abase-stabile, acid-labile ether-forming group, preferablytetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl, most preferablytetrahydropyranyl; R² is a base-labile ether-forming group, preferably--SiR₄ R₅ R₆ wherein R₄, R₅ and R₆ are the same or different and arealkyl of 1-6 carbon atoms, phenyl or arylalkyl such as phenylalkyl,alkyl-substituted-phenylalkyl or naphthylalkyl except that all three maynot be simultaneously methyl, most preferably t-butyldimethylsilyl; andX is hydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy,preferably hydrogen.
 37. A process for preparing a compound of theformula ##STR31## or a racemic or non-racemic mixture thereof wherein R¹is a base-stabile, acid-labile ether-forming group, preferablytetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl, most preferablytetrahydropyranyl; R² is a base-labile ether-forming group, preferably--SiR₄ R₅ R₆ wherein R₄, R₅ and R₆ are the same or different and arealkyl of 1-6 carbon atoms, phenyl or arylalkyl such as naphthylalkylexcept that all three may not be simultaneously methyl, most preferablyt-butyldimethylsilyl; X is hydrogen, halo, trifluoromethyl, lower alkylor lower alkoxy, preferably hydrogen, which process comprises oxidizingwith a chromium-based mild oxidant a compound of the formula ##STR32##or a racemic or non-racemic mixture thereof, wherein R¹, R² and X aredefined above.
 38. The process of claim 37 wherein the oxidant ischromium trioxide in the presence of 3,5-dimethylpyrazole or Collinsreagent (chromium trioxide and pyridine).
 39. A process for preparing acompound of the formula ##STR33## or a racemic or non-racemic mixturethereof wherein R¹ is a base-stabile, acid-labile ether-forming group,preferably tetrahydropyranyl, tetrahydrofuranyl or 2-ethoxyethyl, mostpreferably tetrahydropyranyl; R² is a base-labile ether-forming group,preferably --SiR₄ R₅ R₆ wherein R₄, R₅ and R₆ are the same or differentand are alkyl of 1-6 carbon atoms, phenyl or arylalkyl such asnaphthylalkyl except that all three may not be simultaneously methyl,most preferably t-butyldimethylsilyl; X is hydrogen, halo,trifluoromethyl, lower alkyl or lower alkoxy, preferably hydrogen, whichprocess comprises reducing a compound of the formula ##STR34## or aracemic or non-racemic mixture thereof, wherein X, R¹, R² are asdescribed above and R is alkyl of 1-6 carbon atoms.
 40. The process ofclaim 39 wherein the reduction is carried out by a reducing agent suchas diisobutylaluminum hydride at low temperature.
 41. A process forpreparing a compound of the formula ##STR35## or a racemic ornon-racemic mixture thereof wherein R¹ is a base-stabile, acid-labileether-forming group, preferably tetrahydropyranyl, tetrahydrofuranyl or2-ethoxyethyl, most preferably tetrahydropyranyl; R² is a base-labileether-forming group, preferably --SiR₄ R₅ R₆ wherein R₄, R₅ and R₆ arethe same or different and are alkyl of 1-6 carbon atoms, phenyl orarylalkyl such as naphthylalkyl except that all three may not besimultaneously methyl, most preferably t-butyldimethylsilyl; X ishydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, preferablyhydrogen, which process comprises reducing a compound of the formula##STR36## or a racemic or non-racemic mixture thereof, wherein R¹, R²and X are as defined above with hydrogen and palladium on bariumsulfate.
 42. A process for preparing a compound of the formula ##STR37##or its counterpart of the unnatural prostaglandin configuration, ormixtures thereof, wherein R is hydrogen or lower alkyl, preferablymethyl; X is hydrogen, halo, trifluoromethyl, lower alkyl or loweralkoxy, preferably hydrogen, and the wavy lines represent the α or βconfiguration with the proviso that when one wavy line is α the other isβ or a pharmaceutically acceptable, non-toxic salt of the compound offormula I wherein R is hydrogen, which process comprises:(a) reacting apropargyl alcohol of the formula ##STR38## or its counterpart of theunnatural prostaglandin configuration, or mixtures thereof, wherein Xand the wavy lines are as defined above, R¹ is a base-stabile,acid-labile ether-forming group and R² is a base-labile ether-forminggroup with a lower trialkyl orthoacetate and a catalytic amount of alower alkanoic acid to obtain a compound of the formula ##STR39## or itscounterpart of the unnatural prostaglandin configuration, or mixturesthereof, wherein X, R¹, R² and the wavy lines are as defined above and Ris an alkyl of 1-6 carbon atoms; and (b) homologating the ester obtainedin step (a) and hydrolyzing the base-labile ether-forming --OR² group toobtain a compound of the formula ##STR40## or its counterpart of theunnatural prostaglandin configuration, or mixtures thereof, where X, R¹and the wavy lines are as defined above, M is an alkali metal; and (c)acidifying the salt obtained in step (b) to obtain the correspondingfree acid, and optionally (d) esterifying the acid obtained in step (c)to obtain a compound of the formula ##STR41## or its counterpart of theunnatural prostaglandin configuration, or mixtures thereof, wherein X,R¹ and wavy lines are as defined above, R is an alkyl of 1-6 carbonatoms, and (e) oxidizing the acid obtained in step (c) or the esterobtained in step (d) to obtain a compound of the formula ##STR42## orits counterpart of the unnatural prostaglandin configuration, ormixtures thereof, wherein X, R¹ and the wavy lines are as defined above,R is hydrogen or an alkyl or 1-6 carbon atoms; and (f) hydrolyzing theprotecting group R¹ in the compound obtained in step (e) with an acid toobtain a compound of the formula ##STR43## or its counterpart of theunnatural prostaglandin configuration, or mixtures thereof, wherein X, Rand the wavy lines are as defined above, and optionally (g) esterifyinga compound obtained in step (f) wherein R is hydrogen to thecorresponding compound wherein R is an alkyl of 1-6 carbon atoms, andoptionally (h) converting a compound of formula I wherein R is hydrogento its corresponding pharmaceutically acceptable, non-toxic salts. 43.The process of claim 42 wherein the homologation step (b) is carried outby(a) reducing a compound of the formula ##STR44## or its counterpart ofthe unnatural prostaglandin configuration, or mixtures thereof, whereinR, R¹, R², X and the wavy lines are as defined in step (a) of claim 42,to a primary alcohol of the formula ##STR45## or its counterpart of theunnatural prostaglandin configuration, or mixtures thereof, wherein X,R¹, R² and the wavy lines are as defined above, and (b) converting thealcohol obtained in preceding step (a) to a compound of the formula##STR46## or its counterpart of the unnatural prostaglandinconfiguration, or mixtures thereof, wherein X, R¹, R² and the wavy linesare as defined above and R³ is lower alkyl of 1-6 carbon atoms, aryl of6-10 carbon atoms, aryl (6-10C) lower alkyl or substituted aryl (6-10C)lower alkyl, and (c) reacting the compound or mixture obtained inpreceding step (b) with an alkali metal cyanide to obtain a compound ofthe formula ##STR47## or its counterpart of the unnatural prostaglandinconfiguration, or mixtures thereof, wherein X, R¹, R² and the wavy linesare as defined above, and (d) hydrolyzing the compound obtained inpreceding step (c) with a strong base to obtain a compound of theformula ##STR48## or its counterpart of the unnatural prostaglandinconfiguration, or mixtures thereof, wherein X, R¹ and the wavy lines areas defined above and M is an alkali metal.
 44. The process of claim 43wherein the reduction step (a) is carried out by using a metal hydride,such as lithium aluminum hydride or diisobutylaluminum hydride in anaprotic polar solvent, preferably under an inert atmosphere at thereflux temperature of the solvent.
 45. The process of claim 43 whereinthe conversion step (b) is carried out by reacting said alcohol with anlower alkyl or aryl sulfonate ester, such as methanesulfonyl chloride orp-toluenesulfonyl chloride, in an organic solvent at a temperaturebetween -40° and 25° C.
 46. The process of claim 43 wherein in step (c)said sulfonate ester is reacted with sodium or potassium cyanide in apolar solvent at a temperature between 50°-120° C.
 47. The process ofclaim 43 wherein in the hydrolysis step (d) the strong base is an alkalimetal hydroxide preferably lithium, sodium or potassium hydroxide. 48.The process of claim 42 wherein the oxidation step (e) is carried out byusing a mild oxidizing agent preferably chromium trioxide in thepresence of 3,5-dimethylpyrazole or Collins reagent in a polar solvent.49. The process of claim 42 wherein the hydrolysis step (f) is carriedout by an alkanoic acid of 1-6 carbon atoms, preferably acetic acid or ahydrogen halide, preferably hydrogen fluoride.
 50. Methyl(4,5,6R,8R)-9-oxo-11a,15a-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13(E)-trienoateof the following formula ##STR49##
 51. The compound of claim 50 incrystalline form.
 52. A process for preparing crystalline compound ofclaim 51, which process comprises cooling an oily material of thecompound of claim 50 to a lower temperature preferably at a temperaturebetween -20° to 0° C.
 53. A pharmaceutical composition for the treatmentor prevention of gastric or duodenal ulcers which comprises atherapeutically effective amount of the compound of claims 50 or 51 inadmixture with one or more pharmaceutically acceptable excipients.
 54. Amethod for treating gastric or duodenal ulcers which method comprisesadministering to a mammal a therapeutically effective amount of thecompound of claims 50 or
 51. 55. The compound of claims 50 or 51prepared according to claim 1-14 or 42-49.
 56. The use of the compoundof claims 50 or 51 in the preparation of a pharmaceutical composition.57. A process according to claims 1-14 or 42-49 wherein the activeingredient of claims 50 or 51 prepared in accordance with claims 1-14 or42-49 is mixed with a pharmaceutically acceptable carrier.